Zh Vyssh Nerv Deiat Im I P Pavlova. 2011 Jan-Feb;61(1):85-93.
[Article in Russian]
Kokhan VS, Bolkunov AV, Ustiugov AA, Van'kin GI, Shelkovnikova TA, Redkozubova OM, Strekalova TV, Bukhman VL,Ninkina NN, Bachurin SO.
Abstract
Gamma(gamma)-synuclein is a member of synuclein family of cytoplasmic and predominantly neuronal proteins found only in vertebrates. Gamma-synuclein is abundant in axons and presynaptic terminals of neurons localized in brain regions involved in emotions, learning and memory. However, the role of gamma-synuclein in these brain functions was not previously assessed. We have demonstrated for the first time that the loss of gamma-synuclein results in a significant increase in the level of orientation response in novel environment and decrease in the level of state anxiety.
Exp Cell Res. 2011 Jun 10;317(10):1330-9. Epub 2010 Oct 23.
Source
Women's Cancer Program, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Abstract
Gamma-synuclein is a neuronal protein found in peripheral and motor nerve systems. It becomes highly expressed in metastatic but not in primary tumor or normal tissues. The close association between gamma-synuclein expression and cancer spreading has been demonstrated in a broad range of malignancies. Our previous study showed that exogenous expression of gamma-synuclein in ovarian and breast cancer cells significantly enhanced cell migration and resistance to paclitaxel-induced apoptotic death. In our current research, we found that gamma-synuclein can affect microtubule properties and act as a functional microtubule associated protein. In vitro assays revealed that gamma-synuclein can bind and promote tubulin polymerization, induce the microtubule bundling and alter microtubule morphology developed in the presence of microtubule associated protein 2 (MAP2). Using cancer cell lysate, gamma-synuclein protein was found to be localized in both cytosolic compartment and extracted cytoskeleton portion. Immunofluorescence staining demonstrated that gamma-synuclein can colocalize with microtubule in HeLa cells and decrease rigidity of microtubule bundles caused by paclitaxel. In human ovarian cancer epithelial A2780 cells, gamma-synuclein overexpression improved cell adhesion and microtubule structure upon paclitaxel treatment. Importantly, it led to microtubule-dependent mitochondria clustering at perinuclear area. These observations suggest that overexpression of gamma-synuclein may reduce cell chemo-sensitivity of tumor cells through decreasing microtubule rigidity. In summary, our studies suggested that gamma-synuclein can directly participate in microtubule regulation.
Copyright © 2011 Elsevier Inc. All rights reserved.
Lipids. 2011 Feb;46(2):121-30. Epub 2010 Oct 21.
Source
School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF103AX, UK. GuschinaIA@cf.ac.uk
Abstract
The well-documented link between α-synuclein and the pathology of common human neurodegenerative diseases has increased attention to the synuclein protein family. The involvement of α-synuclein in lipid metabolism in both normal and diseased nervous system has been shown by many research groups. However, the possible involvement of γ-synuclein, a closely-related member of the synuclein family, in these processes has hardly been addressed. In this study, the effect of γ-synuclein deficiency on the lipid composition and fatty acid patterns of individual lipids from two brain regions has been studied using a mouse model. The level of phosphatidylserine (PtdSer) was increased in the midbrain whereas no changes in the relative proportions of membrane polar lipids were observed in the cortex of γ-synuclein-deficient compared to wild-type (WT) mice. In addition, higher levels of docosahexaenoic acid were found in PtdSer and phosphatidylethanolamine (PtdEtn) from the cerebral cortex of γ-synuclein null mutant mice. These findings show that γ-synuclein deficiency leads to alterations in the lipid profile in brain tissues and suggest that this protein, like α-synuclein, might affect neuronal function via modulation of lipid metabolism.
Arch Neurol. 2010 Aug;67(8):970-5.
Nishioka K, Wider C, Vilariño-Güell C, Soto-Ortolaza AI, Lincoln SJ, Kachergus JM, Jasinska-Myga B, Ross OA, Rajput A,Robinson CA, Ferman TJ, Wszolek ZK, Dickson DW, Farrer MJ.
Source
Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.
Abstract
OBJECTIVE:
To determine the association of the genes that encode alpha-, beta-, and gamma-synuclein (SNCA, SNCB, and SNCG, respectively) with diffuse Lewy body disease (DLBD).
DESIGN:
Case-control study. Subjects A total of 172 patients with DLBD consistent with a clinical diagnosis of Parkinson disease dementia/dementia with Lewy bodies and 350 clinically and 97 pathologically normal controls.
INTERVENTIONS:
Sequencing of SNCA, SNCB, and SNCG and genotyping of single-nucleotide polymorphisms performed on an Applied Biosystems capillary sequencer and a Sequenom MassArray pLEX platform, respectively. Associations were determined using chi(2) or Fisher exact tests.
RESULTS:
Initial sequencing studies of the coding regions of each gene in 89 patients with DLBD did not detect any pathogenic substitutions. Nevertheless, genotyping of known polymorphic variability in sequence-conserved regions detected several single-nucleotide polymorphisms in the SNCA and SNCG genes that were significantly associated with disease (P = .05 to <.001). Significant association was also observed for 3 single-nucleotide polymorphisms located in SNCB when comparing DLBD cases and pathologically confirmed normal controls (P = .03-.01); however, this association was not significant for the clinical controls alone or the combined clinical and pathological controls (P > .05). After correction for multiple testing, only 1 single-nucleotide polymorphism in SNCG (rs3750823) remained significant in all of the analyses (P = .05-.009).
CONCLUSION:
These findings suggest that variants in all 3 members of the synuclein gene family, particularly SNCA and SNCG, affect the risk of developing DLBD and warrant further investigation in larger, pathologically defined data sets as well as clinically diagnosed Parkinson disease/dementia with Lewy bodies case-control series.
J Biol Chem. 2010 Oct 1;285(40):30480-8. Epub 2010 Jul 29.
Source
State Key Laboratory of Biotherapy, Section of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract
Insulin-like growth factor (IGF) system plays important roles in carcinogenesis and maintenance of the malignant phenotype. Signaling through the IGF-I receptor (IGF-IR) has been shown to stimulate the growth and motility of a wide range of cancer cells. γ-synuclein (SNCG) is primarily expressed in peripheral neurons but also overexpressed in various cancer cells. Overexpression of SNCG correlates with tumor progression. In the present study we demonstrated a reciprocal regulation of IGF-I signaling and SNCG expression. IGF-I induced SNCG expression in various cancer cells. IGF-IR knockdown or IGF-IR inhibitor repressed SNCG expression. Both phosphatidylinositol 3-kinase and mitogen-activated protein kinase were involved in IGF-I induction of SNCG expression. Interestingly, SNCG knockdown led to proteasomal degradation of IGF-IR, thereby decreasing the steady-state levels of IGF-IR. Silencing of SNCG resulted in a decrease in ligand-induced phosphorylation of IGF-IR and its downstream signaling components, including insulin receptor substrate (IRS), Akt, and ERK1/2. Strikingly, SNCG physically interacted with IGF-IR and IRS-2. Silencing of IRS-2 impaired the interaction between SNCG and IGF-IR. Finally, SNCG knockdown suppressed IGF-I-induced cell proliferation and migration. These data reveal that SNCG and IGF-IR are mutually regulated by each other. SNCG blockade may suppress IGF-I-induced cell proliferation and migration. Conversely, IGF-IR inhibitors may be of utility in suppressing the aberrant expression of SNCG in cancer cells and thereby block its pro-tumor effects.
Addict Biol. 2011 Jan;16(1):120-3. doi: 10.1111/j.1369-1600.2010.00232.x.
Source
Institute of Biochemistry, University of Fribourg, Switzerland.
Abstract
Except as a marker of cancer progression, gamma-synuclein (GSyn) had received little attention. Recent data showed however that GSyn modulates cocaine-induced locomotor effects, suggesting that it could also play a role in cocaine reinforcing effects. In the rat, siRNAs targeting GSyn expression were injected in the nucleus accumbens and cocaine reinforcing effects were evaluated by means of intravenous self-administration. A dose-response curve was followed by procedures of progressive ratio, extinction, cocaine- and cue-induced reinstatements. Decrease of GSyn expression increased self-administration over a large range of doses. This effect was associated with an increase in cocaine-induced reinstatement. The present data reveal that GSyn exert a specific negative control on cocaine-induced reinforcing and incentive effects.
© 2010 The Authors. Addiction Biology © 2010 Society for the Study of Addiction.
Zhonghua Wei Chang Wai Ke Za Zhi. 2010 Jun;13(6):440-4.
[Article in Chinese]
Source
Department of General Surgery, Ruijin Hospital, Shanghai Minimally Invasive Surgery Center, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Abstract
OBJECTIVE:
To explore the relationship between gamma-synuclein gene expression and CpG island demethylation in colorectal cancer(CRC), and the relationship between the demethylation and clinicopathological factors of CRC.
METHODS:
The expression of gamma-synuclein mRNA was examined in 30 pairs of tumor tissues and tumor-matched non-neoplastic adjacent tissues(NNAT) by RT-PCR. CRC cell lines including COLO205, LoVo, and SW480 were used and treated with a demethylating agent, 5-aza-2'-deoxycytidine(5-aza-C). Before and after the treatment, the expression ofgamma-synuclein mRNA in the cells was determined by RT-PCR, and bisulfite sequencing PCR was also used to analyze methylation status of CpG island. The methylation status of gamma-synuclein was then examined in 67 CRC samples and 30 NNAT samples by nested methylation-specific PCR (NMSP) and real time methylation-specific PCR(real-time MSP). The relationship between the demethylation of gamma-synuclein in CRC and clinicopathological factors was analyzed.
RESULTS:
The mean gamma-synuclein mRNA expression was 0.66+/-0.34 in CRC samples, which was much higher than 0.45+/-0.26 in NNAT samples(P=0.011). 5-aza-C could induce expression and demethylation of gamma-synucleinin COLO205, LoVo and SW480 cells. gamma-Synuclein gene was demethylated in 80.0%(24/30) of the CRC samples and 50.0%(15/30) of the NNAT samples. The demethylated status of gamma-synuclein was much higher in CRC samples than that in NNAT samples(P=0.030), and was significantly correlated with clinical stage, lymph node involvement, and distant metastasis of CRC(P<0.05).
CONCLUSION:
The upregulation of gamma-synuclein expression in CRC is primarily attributed to the demethylation of CpG island, which may be used as a marker for prognosis.
J Mol Model. 2011 Feb;17(2):251-63. Epub 2010 May 2.
Source
Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India.
Abstract
Aberrantly expressed human gamma synuclein (SNCG) interacts with BubR1 and heat shock protein 70 (Hsp70) in late stages of breast and ovarian cancer. This interaction is essential for progression, development and survival of cancer cells. A short, synthetically designed ankyrin-repeat-containing peptide (ANK peptide) was proven to inhibit the activity of SNCG. However, the potential binding site residues of SNCG responsible for its oncogenic function have not been reported so far. The objectives of this study were to generate a three-dimensional model of SNCG and to identify the key residues involved in interaction with BubR1, ANK peptide and Hsp70. Our study is the first attempt to report the specific binding of SNCG with the TPR motif of BubR1 and the 18kDa region of Hsp70. Our findings provide novel insights into the mechanism of interaction of SNCG, and can act as a basis for the ongoing drug design and discovery process aimed at treating breast and ovarian cancer.
Oncol Rep. 2010 Feb;23(2):429-36.
Source
Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
Abstract
The synucleins (alpha-, beta- and gamma-synuclein) are a small, soluble, highly conserved group of neuronal proteins that attracted considerable attention due to their involvement in both neurodegenerative diseases and cancer. In this study, we examined the synuclein exprsssion in colorectal cancer (CRC) tissues, tumor-matched non-neoplastic adjacent tissues (NNAT), and CRC cell lines, and then investigated clinical significance of synucleins. By using semi-quantitative RT-PCR, synuclein mRNA expression was detected in eight CRC cell lines. It was much higher in CRC samples than in NNAT samples (P<0.05). The results of western blotting showed that the levels of synucleins protein expression in CRC cells approximately corresponded to the levels of synuclein mRNA expression. Immunohistochemical staining revealed that gamma-synuclein protein expression was up-regulated in CRC samples compared to NNAT samples (P=0.022), and was significantly correlated with clinical stage and lymph node involvement of CRC (P<0.05). Although, there was no significant difference in either alpha- or beta-synuclein protein expression between tumor and normal samples (P>0.05), often more than one form of synuclein was expressed in a tumor sample. More ratios of later stage and lymph node-positive tumors expressed a least one type of synuclein protein, and more ratios showed positive for either alpha or gamma-synuclein expression, as well as positive either for beta or gamma-synuclein in more ratios of lymph node-positive tumors. These results show that alpha-, beta- and gamma-synuclein are expressed in a high percentage of CRC. gamma-synuclein protein is valuable for evaluation of progression of CRC, and it is more sensitive to predict advanced stage and lymph node invasion by detection of gamma-synuclein protein combined with either alpha- or beta-synuclein protein or both than by detection of gamma-synuclein only.
World J Gastroenterol. 2009 Oct 28;15(40):5035-43.
Source
Shanghai Institute of Digestive Surgery, No. 197 Ruijin Second Road, Shanghai 200025, China.
Abstract
AIM:
To investigate the expression pattern of gamma-synuclein in colorectal cancer (CRC) tissues, and to study the effects of gamma-synuclein on CRC cell line HCT116 biological features in vitro.
METHODS:
The expression pattern of gamma-synuclein was determined in 54 CRC tissues and 30 tumor-matched nonneoplastic adjacent tissues (NNAT) 5 cm away from the tumor via real-time quantitative reverse transcription PCR (RT-PCR) and immunohistochemistry. The relationship between gamma-synuclein protein expression and clinicopathological factors of CRC tissues was analyzed. Three small interfering RNA (siRNA) targeting gamma-synuclein mRNA plasmids were constructed and transfected into the CRC cell line HCT116. The stable cell lines were selected with G-418 for 28 d, and the biological features of these cells were examined by cell growth curve, soft agar assay, and cell migration and invasion assays in vitro.
RESULTS:
The expression of gamma-synuclein mRNA and protein was much higher in CRC tissue samples than in NNAT samples (P = 0.02, P = 0.036). There was a significant correlation between the gamma-synuclein protein expression and clinical stage and lymph node involvement of CRC (P = 0.02, P = 0.033). In functional analysis we found that down-regulation of gamma-synuclein expression in HCT116 cells could inhibit the growth, colony formation rate, and migration and invasion ability of HCT116 cells.
CONCLUSION:
Increased expression of gamma-synuclein in CRC tissues and the biological effects of reduced gamma-synuclein expression on HCT116 cells suggest that gamma-synuclein may play a positive role in the progression of CRC.
Neurosci Lett. 2009 Dec 25;467(2):86-9. Epub 2009 Oct 8.
Source
Department of Biochemistry and Molecular and Cell Biology, Georgetown University Medical Center, Georgetown University, Washington, DC 20007, United States.
Abstract
The high incidence of depression in Parkinson's disease (PD) has been well documented in the clinic; however, the underlying molecular mechanisms of these overlapping pathologies remain elusive. Using a rodent model of depression, the Wistar-Kyoto (WKY) rat, we previously demonstrated that in the frontal cortex the altered expression and protein interactions of alpha- and gamma-synuclein (alpha-Syn, gamma-Syn) were associated with dysregulated trafficking of the norepinephrine transporter (NET). Chronic treatment with desipramine (DMI), a NET-selective antidepressant, caused a disappearance of depressive-like behavior that was accompanied by a change in alpha-Syn and gamma-Syn expression and their trafficking of NET. Using this same model, we examined the expression of NET, alpha-Syn and gamma-Syn in the hippocampus, amygdale, brainstem, and striatum, all regions implicated in the development or maintenance of depression or PD pathology. Following chronic treatment with DMI, we observed a significant decrease in NET in the hippocampus, amygdala, and brainstem; decrease in gamma-Syn in the hippocampus and amygdala; and, increase in alpha-Syn in the hippocampus and amygdala. Unexpectedly, we observed a significant decrease in alpha-Syn expression in the striatum of the WKY following chronic DMI treatment. The altered expression of NET, alpha-Syn and gamma-Syn in different brain suggest that DMI's ability to improve depressive-like behavior in a rodent is associated with region-specific changes in the regulation of NET by alpha- and gamma-Syn.
Neurosci Lett. 2009 Apr 10;453(3):157-61. Epub 2009 Feb 21.
Source
Department of Biochemistry, Georgetown University, Washington, DC 20007, USA.
Abstract
Human alpha-synuclein (alpha-Syn) is instrumental in maintaining homeostasis of monoamine neurotransmitters in brain, through its trafficking, and regulation of the cell surface expression and, thereby, activity of dopamine, serotonin and norepinephrine transporters. Here we have investigated whether other members of the synuclein family of proteins,gamma-synuclein (gamma-Syn) and beta-synuclein (beta-Syn) can similarly modulate the serotonin transporter (SERT). In Ltk(-) cells co-transfected with SERT and gamma-Syn, gamma-Syn reduced [(3)H]5-HT uptake, in a manner dependent on its expression levels. The decrease in SERT activity was via decreased V(max) of the transporter, without change in K(m), compared to cells expressing only SERT. By contrast, beta-Syn co-expression failed to alter SERT uptake activity, and neither the V(max) nor the K(m) was changed in the presence of beta-Syn. gamma-Syn modulation of SERT was only partial, with a maximal approximately 27% decrease in SERT activity seen even at high expression levels of gamma-Syn. By contrast, alpha-Syn attenuated SERT activity by approximately 65% at identical expression levels as gamma-Syn. Co-immunoprecipitation studies showed the presence of heteromeric protein:protein complexes between gamma-Syn or alpha-Syn and SERT, while beta-Syn failed to physically interact with SERT. Both alpha-Syn and gamma-Syn colocalized with SERT in rat primary raphae nuclei neurons. These studies document a novel physiological role for gamma-Syn in regulating 5-HT synaptic availability and homeostasis, and may be of relevance in depression and mood disorders, where SERT function is dysregulated.
Cancer Sci. 2008 Oct;99(10):1924-32.
Source
Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Abstract
Recent evidence suggests that gamma-synuclein is abnormally expressed in a high percentage of tumor tissues of diversified cancer types, but rarely expressed in tumor-matched non-neoplastic adjacent tissues (NNAT). The molecular mechanism of CpG island demethylation may underlie aberrant gamma-synuclein expression. To fully understand the roles of aberrant gamma-synuclein expression and demethylation in the development of colorectal cancer (CRC), we examined the expression and methylation status of gamma-synuclein in 67 CRC samples, 30 NNAT samples, and five CRC cell lines as well. By using reverse transcription-polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry analyses, gamma-synuclein expression was detected in both HT-29 and HCT116 cells, and was much higher in CRC samples than in NNAT samples (P < 0.05). The demethylating agent, 5-aza-2 cent-deoxycytidine, can induce re-expression of gamma-synuclein in COLO205, LoVo, and SW480 cells. Unmethylated gamma-synucleinalleles were detected in HT-29, HCT116, and LoVo cells by nested methylation-specific PCR, and the demethylated status of gamma-synuclein was much higher in CRC samples than in NNAT samples by real-time quantitative methylation-specific PCR (P < 0.05). The results of genomic bisulfite DNA sequencing further confirmed that the aberrantgamma-synuclein expression in CRC was primarily attributed to the demethylation of CpG island. The protein expression and demethylation status of gamma-synuclein in 67 CRC samples correlated with clinical stage, lymph node involvement, and distant metastasis. These findings suggest an involvement of aberrant gamma-synuclein expression and demethylation in progression of CRC, especially in advanced stages.
J Pathol. 2009 Mar;217(4):507-15.
Source
Division of Signal Transduction and Molecular Targeting Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Abstract
Previous studies have demonstrated that gamma-synuclein is overexpressed in a variety of human malignancies. Overexpression of gamma-synuclein in human breast cancer cells leads to an increase in cell motility, resistance to chemotherapeutic drugs, and mitotic checkpoint dysfunction. We report in this study that gamma-synuclein is up-regulated by endoplasmic reticulum stress. The up-regulation of gamma-synuclein expression by endoplasmic reticulum stress is mediated, at least in part, by activation transcription factor (ATF) 4. Knockdown of gamma-synucleinsensitized human breast cancer cells to endoplasmic reticulum stress-induced apoptosis. Induction of apoptosis by endoplasmic reticulum stress when gamma-synuclein was inhibited was dependent on JNK or caspase activation, with caspase-3 and caspase-7 being involved. Treatment with the JNK or caspase-3 and caspase-7 inhibitor partially blocked endoplasmic reticulum stress-induced apoptosis in breast cancer cells transfected with or without the siRNA againstgamma-synuclein. Taken together, these data suggest that gamma-synuclein may promote cancer progression by suppressing endoplasmic reticulum stress-induced apoptosis.
J Biol Chem. 2008 Dec 26;283(52):36377-85. Epub 2008 Oct 20.
Source
Laboratory of Retinal Biology, Veterans Affairs Medical Center, Kansas City, Missouri 64128, USA.
Abstract
gamma-Synuclein (Syn G) is highly expressed in retinal ganglion cells and the loss of these cells in glaucoma is associated with significant reduction of the intracellular Syn G level. However, a causative relationship between these two events has not been established. Here we show that the knockdown of Syn G results in a decreased viability of the immortalized retinal ganglion cells (RGC-5). The Syn G silencing reduces phosphorylation of serine 112 (Ser112) in Bad protein, a member of the Bcl-2 family that plays a critical role in apoptotic cell death signaling. Our gene expression analysis data suggests that changes in Bad phosphorylation status may be caused by a coordinated shift in activities of kinases controlling Bad phosphorylation and phosphatases catalyzing its dephosphorylation. Moreover, increased phosphorylation of Bad-sequestering protein 14-3-3 detected in these cells is also pro-apoptotic. These results suggest that the homeostatic level of Syn G in RGC-5 cells is required for transcriptional regulation of protein kinases and phosphatases, controlling phosphorylation of Bad and 14-3-3. Lowering Syn G causes Bad dephosphorylation, dissociation from phosphorylated 14-3-3, and translocation to mitochondria where it initiates apoptotic death cascade.
Mol Hum Reprod. 2008 Nov;14(11):655-63. Epub 2008 Oct 10.
Singh MN, Stringfellow HF, Taylor SE, Ashton KM, Ahmad M, Abdo KR, El-Agnaf OM, Martin-Hirsch PL, Martin FL.
Source
Lancashire Teaching Hospitals NHS Trust, Fulwood, Preston, UK.
Abstract
Endometriosis is a debilitating disease in which apoptotic, genetic, immunological, angiogenic and environmental factors have been implicated. Endocrine-disrupting agents (e.g. dioxins) might be involved. Dioxins, via the arylhydrocarbon receptor (AhR), induce estrogen-metabolizing enzymes CYP1A1 and CYP1B1. Elevated expression ofgamma-SYNUCLEIN (gamma-SYN) has been associated with hormone-related conditions. Tissue sets consisting of eutopic and ectopic (ovarian) endometrium from patients with stage 3 or 4 endometriosis were obtained. Following RNA extraction and reverse transcription, quantitative real-time reverse transcriptase-polymerase chain reaction was performed for anti-apoptotic B-cell leukaemia/lymphoma 2 (BCL-2), CYP1A1, CYP1B1, estrogen receptor (ER)alpha, ER beta and gamma-SYN. Immunohistochemical analyses for gamma-syn, ER alpha, ER beta and CYP1A1 were also conducted. A 3-9-fold increase in intra-individual expression of CYP1A1 in ectopic (ovarian) endometrium compared with eutopic tissue was observed; immunohistochemical analyses pointed to CYP1A1 being localized to the glandular epithelium. This intra-individual expression profile was not observed for CYP1B1 or BCL-2. However, a 5-53-fold intra-individual increase in gamma-SYN expression was also demonstrated in six of nine tissue sets (a further two showed an increase that was not considered significant) when comparing ectopic to eutopic endometrium; gamma-syn positivity was associated with endothelial cells. An elevation in ER beta was also noted when comparing ectopic to eutopic endometrium; with regard to ER alpha, this was inconsistent. These results suggest an up-regulation of dioxin-inducible CYP1A1 and gamma-SYN occurs in endometriosis. Whether gamma-syn may be a novel diagnostic marker for endometriosis remains to be ascertained.
Neuropsychopharmacology. 2009 Mar;34(4):987-98. Epub 2008 Sep 17.
Source
Department of Biochemistry and Molecular and Cell Biology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA.
Abstract
The mechanisms underlying depression remain elusive. We previously determined that alpha-synuclein (alpha-Syn) modulates the activity and trafficking of the norepinephrine transporter (NET) in a manner that is dependent on its interactions with microtubules (MTs). Here we sought to determine if alpha-Syn, or the other synuclein family members, beta-synuclein (beta-Syn) and gamma-synuclein (gamma-Syn), modulate NET activity in an animal model of depression, the Wistar-Kyoto (WKY) rat. The NET-selective antidepressant desipramine (DMI) was chronically administered for 14 days to WKY rats and the strain from which it was outbred that does not show depressive-like behavior, the Wistar rat. This drug regimen induced significant behavioral improvements in the WKY, but not the Wistar rat, in the forced swim test. In WKY rats there was an overexpression of gamma-Syn which was reduced following DMI treatment. In parallel, DMI caused an increase in both alpha-Syn and NET in the frontal cortex. Frontal cortex synaptosomes from WKY rats were not sensitive to nocodazole, a compound that promotes MT destabilization. However, in WKYs treated with DMI, nocodazole induced an increase in [(3)H]-NE uptake. This trend was reversed in Wistars. Underlying these DMI-induced changes were alterations in the protein interactions between the synucleins and NET with the tubulins. These results are the first to implicate alpha-Syn or gamma-Syn in the pathophysiology of depression and suggest that targeting synucleins may provide a new therapeutic option for depression.
Mol Vis. 2008 Aug 22;14:1540-8.
Source
Retinal Biology Research Laboratory, Veterans Administration Medical Center, Kansas City, MO 64128, USA.
Abstract
PURPOSE:
Previous studies have described gamma-synuclein as a protein highly expressed in retinal ganglion cells (RGCs), and a loss of RGCs correlates with a downregulation of gamma-synuclein gene expression in glaucoma. Here we asked whether gamma-synuclein expression in the retina can be considered a specific marker of RGCs.
METHODS:
gamma-Synuclein expression was examined with immunohistochemistry in retinal sections from normal and glaucomatous human eyes. Primary cultures of RGCs from Sprague-Dawley rats purified by sequential immunopanning using a monoclonal antibody to Thy1-1, cultures of A7 immortalized optic nerve astrocytes from newborn rats, and the immortalized RGC-5 cell line were studied using immunofluorescence and quantitative RT-PCR.
RESULTS:
gamma-Synuclein was highly expressed in RGCs in the human retina and was localized in cytoplasm adjacent to the RGC nuclear marker, Brn-3a. Axons of RGCs were immunopositive for gamma-synuclein in the nerve fiber layer (NFL), the lamina cribrosa and the retrobulbar optic nerve. In the optic nerve of glaucoma patients, axon swellings were likewise immunopositive, whereas in the retina of patients with retinoblastoma, NFL staining appeared reduced. In primary rat RGCs and in immortalized RGC-5 cultures, gamma-synuclein was localized predominantly in the perinuclear area and in cell processes. Among rat retinal cells in culture, all Brn-3a positive cells were stained with agamma-synuclein antibody; rare gamma-synuclein-positive cells were not stained by the Brn-3a antibody.
CONCLUSIONS:
gamma-Synuclein is selectively and abundantly expressed in human RGCs in vivo, primary rat RGCs in vitro, and immortalized RGC-5 cells. In pathology, gamma-synuclein abundance may vary between RGC somas and axons. Coincident Brn-3a and gamma-synuclein expression suggests that strong gamma-synuclein expression can be considered a marker of RGCs. Future translational approaches might include using a gamma-synuclein promoter for the specific delivery of siRNA or therapeutic proteins to RGCs.
Eur J Neurosci. 2008 Jun;27(11):2938-51.
Source
Institute of Biochemistry, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland.
Erratum in
· Eur J Neurosci. 2008 Sep;28(5):1031.
Abstract
The aim of this study was to investigate the role of gamma-synuclein in the rewarding effects of chronic cocaine administration and its putative interaction with the dopamine transporter (DAT). For this purpose, regulatable lentiviruses driving overexpression of the rat gamma-synuclein or DAT have been prepared, as well as lentiviruses expressing siRNAs, aimed at silencing either DAT or gamma-synuclein mRNA expression. Overexpression of DAT in the nucleus accumbens (NAc) induced a 35% decrease in locomotor activity, which could be abolished when the same animal was fed doxycycline. Furthermore, local inhibition of DAT in the NAc, using lentiviruses expressing siRNAs targeted against DAT, resulted in significant hyperlocomotion activity (72% increase over controls). By contrast, overexpression of gamma-synuclein in the NAc alone had no effect, while local silencing lead to a significant decrease in cocaine-induced locomotor activity (47% decrease compared with controls). Surprisingly, coinjection lentiviruses expressing DAT andgamma-synuclein - leading to overexpression of both proteins in the NAc - resulted in a strong increase in cocaine-induced rat locomotor activity (52% increase compared with controls), which was abolished upon locally silencing these genes, suggesting a synergetic role of both proteins, possibly mediated through a direct interaction.
Dement Geriatr Cogn Disord. 2008;26(1):32-42. Epub 2008 Jun 25.
Mukaetova-Ladinska EB, Milne J, Andras A, Abdel-All Z, Cerejeira J, Greally E, Robson J, Jaros E, Perry R, McKeith IG,Brayne C, Xuereb J, Cleghorn A, Doherty J, McIntosh G, Milton I.
Source
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. Elizabeta.Mukaetova-Ladinska@ncl.ac.uk
Abstract
BACKGROUND:
Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease alpha-synuclein is incorporated within Lewy bodies and alpha-, beta- and gamma-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF.
METHODS:
A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify alpha- and gamma-synucleins and IgG.
RESULTS:
We describe for the first time the presence of gamma-synuclein in CSF. There is an elevation of both alpha- and gamma-synucleins in CSF from elderly individuals with Alzheimer's disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. gamma-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of alpha- and gamma-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay.
CONCLUSIONS:
The reported increases in alpha- and gamma-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.
Copyright 2008 S. Karger AG, Basel.
J Mol Neurosci. 2008 Jul;35(3):267-71. Epub 2008 May 23.
Source
Retinal Biology Research Laboratory, Veterans Administration Medical Center, 4801 East Linwood Boulevard, Kansas City, MO 64128, USA.
Abstract
Gamma-synuclein, also referred to as breast-cancer-specific gene 1, is the third member of the neuronal protein family synuclein. Synucleins attracted the attention of many investigators because of their role in human diseases. Gamma-synuclein participates in the pathogenesis of several types of cancer and some neurodegenerative diseases. Its role in tumorigenesis is due to the upregulation of transcription and the effect on downstream targets, including signaling pathways and transcription factors. Gamma-synuclein is also expressed in neurons and glial cells, but the regulation of its expression, as well as the mechanism of transition from normal functions to pathology in these cell types, is not studied. Here, we examined how gamma-synuclein promoter is regulated in neuronal and glial cells. We also show thatgamma-synuclein is able to bind directly to several transcription factors. These results are discussed in connection with the implication of gamma-synuclein in diseases.
Mol Biol Rep. 2009 May;36(5):971-9. Epub 2008 May 7.
Source
Department of Genetics and Biotechnology, Faculty of Agricultural Sciences, University of Aarhus, Blichers Alle 20, Tjele, Denmark.
Abstract
The gamma-synuclein protein is involved in breast carcinogenesis and has also been implicated in other forms of cancer and in ocular diseases. Furthermore, gamma-synuclein is believed to have a role in certain neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. This work reports the cloning and characterization of the porcine (Sus scrofa) gamma-synuclein cDNA (SNCG). The SNCG cDNA was amplified by reverse transcriptase polymerase chain reaction (RT-PCR) using oligonucleotide primers derived from in silico sequences. The porcine SNCG cDNA codes for a protein of 126 amino acids which shows a high similarity to bovine (90%), human (87%) and mouse (83%) gamma-synuclein. A genomic clone containing the entire porcine SNCG gene was isolated and its genomic organization determined. The gene is composed of five exons, the general structure being observed to be very similar to that of the human SNCG gene. Expression analysis by quantitative real-time RT-PCR revealed the presence of SNCG transcripts in all examined organs and tissues. Differential expression was observed, with very high levels of SNCG mRNA in fat tissue and high expression levels in spleen, cerebellum, frontal cortex and pituitary gland. Expression analysis also showed that porcine SNCG transcripts could be detected in different brain regions during early stages of embryo development. The porcine SNCG orthologue was mapped to chromosome 14q25-q29. The distribution of recombinant porcine gamma-synuclein was studied in three different transfected cell lines and the protein was found to be predominantly localized in the cytoplasm.
J Nutr. 2008 May;138(5):841-8.
Oort PJ, Knotts TA, Grino M, Naour N, Bastard JP, Clément K, Ninkina N, Buchman VL, Permana PA, Luo X, Pan G, Dunn TN, Adams SH.
Source
USDA/Agricultural Research Service Western Human Nutrition Research Center, Davis, CA 95616, USA.
Abstract
Recently, we characterized tumor suppressor candidate 5 (Tusc5) as an adipocyte-neuron PPARgamma target gene. Our objective herein was to identify additional genes that display distinctly high expression in fat and neurons, because such a pattern could signal previously uncharacterized functional pathways shared in these disparate tissues. gamma-Synuclein, a marker of peripheral and select central nervous system neurons, was strongly expressed in white adipose tissue (WAT) and peripheral nervous system ganglia using bioinformatics and quantitative PCR approaches. Gamma-synuclein expression was determined during adipogenesis and in subcutaneous (SC) and visceral adipose tissue (VAT) from obese and nonobese humans. Gamma-synuclein mRNA increased from trace levels in preadipocytes to high levels in mature 3T3-L1 adipocytes and decreased approximately 50% following treatment with the PPARgamma agonist GW1929 (P < 0.01). Because gamma-synuclein limits growth arrest and is implicated in cancer progression in nonadipocytes, we suspected that expression would be increased in situations where WAT plasticity/adipocyte turnover are engaged. Consistent with this postulate, human WAT gamma-synuclein mRNA levels consistently increased in obesity and were higher in SC than in VAT; i.e. they increased approximately 1.7-fold in obese Pima Indian adipocytes (P = 0.003) and approximately 2-fold in SC and VAT of other obese cohorts relative to nonobese subjects. Expression correlated with leptin transcript levels in human SC and VAT (r = 0.887; P < 0.0001; n = 44). Gamma-synuclein protein was observed in rodent and human WAT but not in negative control liver. These results are consistent with the hypothesis that gamma-synuclein plays an important role in adipocyte physiology.
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Eur J Neurosci. 2008 Feb;27(4):947-57.
Source
Wellcome Trust Centre For Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Abstract
Alpha-synuclein is intimately involved in the pathogenesis of Parkinson's disease, and has been implicated in the regulation of synthesis, release and reuptake of dopamine (DA). However, mice lacking members of the synuclein family have been reported to display no overt behavioural phenotype. This may be a result of compensatory upregulation of other synucleins during development. Here we report on behaviour and DA synapse function of alpha-synuclein null,gamma-synuclein null, and alpha-gamma-synuclein double-null knockout mice. Double-null mice were hyperactive in a novel environment and alternated at a lower rate in a T-maze spontaneous alternation task, a phenotype reminiscent of mice expressing reduced levels of the DA transporter. To investigate a possible hyperdopaminergic phenotype in alpha-gamma-synuclein double-null mice, we used fast-scan cyclic voltammetry at carbon-fibre microelectrodes to assess DA release and reuptake in striatal slices from wild-type, alpha-null, gamma-null and double-null mice in real time. Double-null mice were found to have a twofold increase in the extracellular concentration of DA detected after discrete electrical stimuli in the striatum. By measuring the rate of reuptake of DA and tissue DA content in these animals, we showed that the observed increase in size of striatal DA transients was not attributable to a decrease in reuptake of DA via the DA transporter, and can not be attributed to an increase in tissue DA levels in the striatum. Rather, we propose that loss of both alpha- and gamma-synuclein causes an increase in release probability from dopaminergic synapses.
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FASEB J. 2007 Nov;21(13):3419-30. Epub 2007 Jun 12.
Source
Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates, Al Ain, PO BOX 17666, United Arab Emirates.
Abstract
The synucleins are a small, soluble, highly conserved group of neuronal proteins that have been implicated in both neurodegenerative diseases and cancer. The synuclein family consists of alpha-, beta-, and gamma-synucleins (gamma-syn). They are a natively unfolded group of proteins that share sequence homologies and structural properties. So far, the biological functions of the synucleins are still unclear, but their involvement in neurodegenerative diseases and cancer may provide insights into the pathological processes that result from these two groups of debilitating diseases, and present the possibility to use them as potential targets for early diagnosis and treatment. Recently, elevated levels of gamma-syn proteins have been detected in various types of cancer, especially in advanced stages of the disease. Furthermore, studies to date indicate that overexpression of gamma-syn compromises normal mitotic checkpoint controls, resulting in multinucleation as well as faster cell growth. Gamma-syn has also been shown to promote invasion and metastasis in in vitro assays as well as in animal models. Overexpression of gamma-syn also interferes with drug-induced apoptotic responses. These observations raise questions about the involvement of gamma-syn in the process of tumorigenesis and metastasis, and efforts have already been made to use gamma-syn as a marker for assessing breast cancer progression. This review will discuss the involvement of gamma-syn in cancer progression, metastasis and its potential as a marker.
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Neurogenetics. 2007 Apr;8(2):71-81. Epub 2007 Feb 22.
Source
Department of Medical Genetics, University of Tuebingen, Calwerstrasse 7, 72076 Tubingen, Germany.
Abstract
alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease. The function of alpha-synuclein has not been deciphered yet; however, it might play a role in vesicle function, transport, or as a chaperone. alpha-Synuclein belongs to a family of three proteins, which includes beta- and gamma-synuclein. gamma-Synuclein shares 60% similarity with alpha-synuclein. Similar to alpha-synuclein, a physiological function for gamma-synuclein has not been defined yet, but it has been implicated in tumorgenesis and neurodegeneration. Interestingly, neither alpha- (SNCA(-/-)), gamma- (SNCG(-/-)), nor alpha/gamma- (SNCA_G(-/-)) deficient mice are present with any obvious phenotype. Using microarray analysis, we thus investigated whether deficiency of alpha- and gamma-synuclein leads to similar compensatory mechanisms at the RNA level and whether similar transcriptional signatures are altered in the brain. Sixty-five genes were differentially expressed in all mice. SNCA(-/-) mice and SNCG(-/-) mice shared 84 differentially expressed genes, SNCA(-/-) and SNCA_G(-/-) expressed 79 genes, and SNCG(-/-) and SNCA_G(-/-) expressed 148 genes. For many of the physiological pathways such as dopamine receptor signaling (down-regulated), cellular development, nervous system function, and cell death (up-regulated), we found groups of genes that were similarly altered in SNCA(-/-) and SNCG(-/-) mice. In one of the pathways altered in both models, we found Mapk1 as the core transcript. Other gene groups, however, such as TGF-beta signaling and apoptosis pathways genes were significantly up-regulated in the SNCA(-/-) mice but down-regulated in SNCG(-/-) mice. beta-synuclein expression was not significantly altered in any of the models.
Protein Sci. 2006 Dec;15(12):2795-804. Epub 2006 Nov 6.
Source
Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Abstract
The synucleins are a family of intrinsically disordered proteins involved in various human diseases. alpha-Synuclein has been extensively characterized due to its role in Parkinson's disease where it forms intracellular aggregates, whilegamma-synuclein is overexpressed in a majority of late-stage breast cancers. Despite fairly strong sequence similarity between the amyloid-forming regions of alpha- and gamma-synuclein, gamma-synuclein has only a weak propensity to form amyloid fibrils. We hypothesize that the different fibrillation tendencies of alpha- and gamma-synuclein may be related to differences in structural propensities. Here we have measured chemical shifts for gamma-synuclein and compared them to previously published shifts for alpha-synuclein. In order to facilitate direct comparison, we have implemented a simple new technique for re-referencing chemical shifts that we have found to be highly effective for both disordered and folded proteins. In addition, we have developed a new method that combines different chemical shifts into a single residue-specific secondary structure propensity (SSP) score. We observe significant differences between alpha- and gamma-synuclein secondary structure propensities. Most interestingly, gamma-synuclein has an increased alpha-helical propensity in the amyloid-forming region that is critical for alpha-synuclein fibrillation, suggesting that increased structural stability in this region may protect against gamma-synuclein aggregation. This comparison of residue-specific secondary structure propensities between intrinsically disordered homologs highlights the sensitivity of transient structure to sequence changes, which we suggest may have been exploited as an evolutionary mechanism for fast modulation of protein structure and, hence, function.
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J Mol Neurosci. 2006;29(3):269-77.
Source
Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Spring House, PA 19477, USA. Emalatyn@PRDUS.jnj.com
Abstract
Synucleins are proteins known for their malfunction in a group of illnesses called synucleopathies, which includes Alzheimer's and Parkinson's disease. To learn more about the role of synucleins in the CNS, we have studied levels of message coding for alpha-, beta-, and gamma-synuclein using quantitative RT-PCR. Levels of synuclein mRNAs were studied in the cerebral cortex (left and right, anterior and posterior), hippocampus, striatum, and cerebellum, obtained from 5-d-old (newborn), 1-mo (juvenile)-, and 6-, and 9-mo (adult)-old rats. The mRNA levels for all synucleins varied significantly among structures. The rank order of mRNA levels in different structures was cortex = hippocampus > striatum > cerebellum for alpha-synuclein; cortex > hippocampus = cerebellum > striatum for beta-synuclein; and hippocampus = striatum > cortex = cerebellum for gamma-synuclein. There was significant effect of age for mRNA levels for all synucleins. The dynamics of these changes were different depending on type of synuclein and brain structure. Levels of mRNA for alpha-synuclein were significantly reduced with age in all structures except hippocampus. For beta- and gamma-synuclein, levels increased significantly only in the cerebral cortex and only from 5 d to 1 mo of age. In contrast, gamma-synuclein levels in the cerebellum were very high at 5 d and significantly reduced at 1 mo of age. The revealed pattern and dynamics of changes in the levels of mRNA coding for synucleins would support the conclusion for an important role of these molecules during development and the aging process.
Oncol Rep. 2006 Jul;16(1):207-12.
Source
Metastasis and Angiogenesis Research Group, Wales College of Medicine, Cardiff University, Heath Park, Cardiff, CF4 4XN, UK. martinta1@cf.ac.uk
Abstract
This study examined the expression and distribution of BCSG-1 in human breast cancer tissue. IHC revealed that BCSG-1 was primarily seen as a cytosolic protein, weakly staining normal mammary epithelial cells but increased in breast tumour cells. Q-PCR revealed that node negative and positive tumours had similar levels of BCSG-1 transcript and BCSG-1/CK19 ratio. There were significantly higher levels in grade 2 and grade 3 tumours compared to grade 1. Patients with NPI (Nottingham prognostic indicator) < 3.4, had a predicted 80% 15-year survival. After a 10-year follow-up, no significant difference was seen between tumours from patients remaining disease-free and those who died of breast cancer. The levels of BCSG-1 significantly correlated with an associated molecule, transglutaminase-3 (r = 0.307, P < 0.05), and weakly with transglutaminase-7 (r = 0.183). BCSG-1 is increased in breast tumour cells, is negatively associated with tumour grade and significantly correlates with levels of transglutaminase-3.
Cell Motil Cytoskeleton. 2006 Aug;63(8):447-58.
Source
Retinal Biology Research Laboratory, Veterans Administration Medical Center, Kansas City, MO 66148, USA. asurguchov@kumc.edu
Abstract
gamma-Synuclein is a member of the synuclein family consisting of three proteins. Within the last several years increasing attention has focused on these proteins because of their role in human diseases. alpha-Synuclein relevance to Parkinson's disease is based on mutations found in familial cases of the disease and its presence in filaments and inclusion bodies in sporadic cases. gamma-Synuclein is implicated in some forms of cancer and ocular diseases, while beta-synuclein may antagonize their pathological functions. In this paper we present data on the localization and properties of gamma-synuclein in several neuronal and nonneuronal cell cultures. We show that contrary to the current opinion, gamma-synuclein is not an exclusively cytoplasmic protein, but has a dynamic localization and can associate with subcellular structures. It is present in the perinuclear area and may be associated to centrosomes. On late steps of mitosis gamma-synuclein is not found in the centrosomes, and redistributes to the midbody in telophase. Under stress conditions a translocation of gamma-synuclein from the perinuclear area to the nucleus occurs exhibiting nucleocytoplasmic shuttling. gamma-Synuclein overexpression reduces neurite outgrowth in a greater extent then alpha-synuclein overexpression. These data support the view that gamma-synuclein may change its intracellular localization and associate with subcellular structures in response to intracellular signaling or stress.
Copyright 2006 Wiley-Liss, Inc.
Protein Sci. 2006 May;15(5):1162-74. Epub 2006 Apr 5.
Source
Department of Biochemistry and Program in Structural Biology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Abstract
We have used solution state NMR spectroscopy to characterize the secondary structure and backbone dynamics of the proteins beta- and gamma-synuclein in their detergent micelle-bound conformations. Comparison of the results with those previously obtained for the Parkinson's disease-linked protein alpha-synuclein shows that structural differences between the three homologous synuclein family members are directly related to variations in their primary amino acid sequences. An 11-residue deletion in the lipid-binding domain of beta-synuclein leads to the destabilization of an entire segment of the micelle-bound helical structure containing the deletion site. The acidic C-terminal tail region of gamma-synuclein, which displays extensive sequence divergence, is more highly disordered than the corresponding regions in the other two family members. The observed structural differences are likely to mediate functional variations between the three proteins, with differences between alpha- and beta-synuclein expected to revolve around their lipid interactions, while differences in gamma-synuclein function are expected to result from different protein-protein interactions mediated by its unique C-terminal tail.
Cell Mol Neurobiol. 2005 Sep;25(6):1009-33.
Source
Retinal Disease Research Laboratory, Veterans Administration Medical Center, 4801 Linwood Blvd, Kansas City, MO 66148, USA.
Abstract
Mutations in the gene encoding human myocilin are associated with some cases of juvenile and early-onset glaucoma. Glaucomatous mutations prevent myocilin from being secreted. The analysis of the defects associated with mutations point to the existence of factor(s) in addition to mutations that might be implicated in the development of glaucoma. In the present paper, we found that interaction of myocilin with one of the members of the synuclein family alters its properties, including its ability to be secreted. Results of immunoprecipitation show that myocilin is a gamma-synuclein-interacting protein. Further analysis demonstrated that both myocilin and gamma-synuclein are expressed in human TM cells, immortalized rat ganglion (RGC-5) cells, and HT22 hippocampal neurons. According to Western blotting, in addition to monomeric form with molecular weight 17 kDa gamma-synuclein is present as higher molecular weight forms ( approximately 35 and 68 KDa), presumably dimer and tetramer. Myocilin and gamma-synuclein have partially overlapping perinuclear localization. Dexamethasone upregulates myocilin expression in RGC-5 cells and HT22 hippocampal neurons. We found alterations of myocilin properties as a result of its interaction with gamma-synuclein. In cultured cells, gamma-synuclein upregulates myocilin expression, inhibits its secretion and prevents the formation of high molecular weight forms of myocilin. Although both alpha-synuclein and gamma-synuclein are expressed in HTM cells, only gamma-synuclein interacts with myocilin and alters its properties. We conclude that myocilin and gamma-synuclein interact and as a result, myocilin's properties are changed. Since myocilin and gamma-synuclein have partially overlapping intracellular localization in cell types that are implicated in glaucoma development, their interaction may play an important role in glaucoma.
Mol Cell Neurosci. 2005 Feb;28(2):326-34.
Source
Laboratory for Molecular Pharmacology, Department of Pharmacology, University College London, UCL, London WC1E 6BT, UK.
Abstract
alpha-Synuclein, a protein implicated in neurodegenerative diseases and of elusive physiological function owes its name to an observed presence in presynaptic and nuclear compartments. However, its nuclear localisation has remained controversial. We expressed synuclein-eGFP fusion proteins in organotypic rat hippocampal slice cultures and murine hippocampal primary neurons using a Sindbis virus expression system. Recombinant full-length alpha-synuclein accumulated in presynaptic locations, mimicking its native distribution. Expression of deletion mutant alpha-synuclein revealed that presynaptic targeting depended on the presence of its N-terminal and core region. This domain also causes nuclear exclusion of the alpha-synuclein fusion protein. In contrast, the C-terminal domain of alpha-synuclein directs fusion proteins into the nuclear compartment. The related protein gamma-synuclein contains a similar N-terminal and core domain as alpha-synuclein. However, gamma-synuclein lacks a C-terminal domain that causes nuclear localisation of the fusion protein, suggesting that the two synucleins might have different roles relating to the cell nucleus.
Genes Brain Behav. 2005 Feb;4(1):60-4.
Source
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477-0776, USA.
Abstract
Synucleins are small proteins regulating the filamentous network that in turn influences the release of dopamine and glutamate neurotransmitters involved in mood and motivation processes. We have studied the pattern of synuclein expression in animal models for mania and depression. Dominant behavior, as defined in a food competition test with dyads of rats, can serve as a model of mania and submissive behavior as a model of depression. The expression of alpha-, beta- and gamma-synuclein was analyzed in four regions of cortex from dominant, neutral and submissive rats using TaqMan reverse transcription-polymerase chain reaction technology. The expression levels of gamma-synucleinwere elevated consistently in all regions of cerebral cortex of dominant rats (P <0.05; 23.5 +/- 1.1, normalized units) in contrast to the submissive rat group (10.3 +/- 1.2). Neutral rats had intermediate cerebral cortex levels of gamma-synuclein expression (15.7 +/- 1.4) that were significantly lower than that in dominant rats (P <0.05). No changes in alpha- or beta-synuclein expression were observed among the groups. These studies indicate that gamma-synucleinlevels in the cerebral cortex were differentially associated with dominant and submissive behavior.
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Am J Respir Cell Mol Biol. 2005 Mar;32(3):192-200. Epub 2004 Dec 23.
Source
Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, 3900 Reservoir Road NW, Washington, DC 20057, USA.
Abstract
Many military personnel are at risk of lung damage or systemic toxicity as a result of exposure to the jet fuel JP-8. We have now used microarray analysis to characterize changes in the gene expression profile of lung tissue induced by exposure of rats to JP-8 at a concentration of 171 or 352 mg/m(3) for 1 h/d for 7 d, with the higher dose estimated to mimic the level of occupational exposure in humans. The expression of 56 genes was significantly affected by a factor of </= 0.6 or >/= 1.5 by JP-8 at the low dose. Eighty-six percent of these genes were downregulated by JP-8. The expression of 66 genes was similarly affected by JP-8 at the higher dose, with the expression of 42% of these genes being upregulated. Prominent among the latter genes was that for the centrosome-associated protein gamma-synuclein, whose expression was consistently increased. The expression of various genes related to antioxidant responses and detoxification, including those for glutathione S-transferases and cytochrome P450 proteins, were also upregulated. The microarray data were confirmed by quantitative RT-PCR analysis. Our extensive data set may thus provide important insight into the pulmonary response to occupational exposure to JP-8 in humans.
Cancer Sci. 2004 Dec;95(12):955-61.
Iwaki H, Kageyama S, Isono T, Wakabayashi Y, Okada Y, Yoshimura K, Terai A, Arai Y, Iwamura H, Kawakita M, Yoshiki T.
Source
Department of Urology, Shiga University of Medical Science, Shiga 520-2192, Japan.
Abstract
Using proteomic analysis, we previously identified calreticulin (CRT) as a potentially useful urinary marker for bladder cancer. Now, we have also identified gamma -synuclein (SNCG) and a soluble isoform of catechol-o-methyltransferase (s-COMT) as novel candidates for tumor markers in bladder cancer, by means of proteomic analysis. In the process of establishing a superior tumor marker system, we investigated the diagnostic value of a combination assay of these three proteins. Voided urine samples were obtained from 112 bladder cancer and 230 control patients. Urinary CRT, SNCG, and s-COMT were measured as a combined marker by quantitative western blot analysis. Relative concentration of each protein was calculated and the diagnostic value of a concomitant examination of these markers was evaluated by receiver operator characteristic analysis. With the best diagnostic cutoff, the overall sensitivity of the combined markers was 76.8% (95% confidence interval, 69-81%) with a specificity of 77.4% (72-80%), while those of a single use of CRT were 71.4% and 77.8%, respectively. When evaluated in relation to tumor characteristics, such as grade, stage, size, and outcome of urinary cytology, the diagnostic capacity of the combined markers was equal to or better than that of CRT in all categories. Concomitant use of CRT, SNCG, and s-COMT had higher sensitivity for detection of bladder cancer than did single use of CRT. Our study suggests that use of this panel of markers will improve the diagnosis of bladder cancer and may allow the development of a protein microarray assay or multi-channel enzyme-linked immunosorbent assay.
J Biol Chem. 2005 Mar 4;280(9):7562-9. Epub 2004 Dec 9.
Snyder H, Mensah K, Hsu C, Hashimoto M, Surgucheva IG, Festoff B, Surguchov A, Masliah E, Matouschek A, Wolozin B.
Source
Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Abstract
The accumulation of aggregated alpha-synuclein is thought to contribute to the pathogenesis of Parkinson's disease. Recent studies indicate that aggregated alpha-synuclein binds to S6', a component of the 19 S subunit in the 26 S proteasome and inhibits 26 S proteasomal degradation, both ubiquitin-independent and ubiquitin-dependent. The IC(50) of aggregated alpha-synuclein for inhibition of the 26 S ubiquitin-independent proteasomal activity is approximately 1 nm. alpha-Synuclein has two close homologues, termed beta-synuclein and gamma-synuclein. In the present study we compared the effects of the three synuclein homologues on proteasomal activity. The proteasome exists as a 26 S and a 20 S species, with the 26 S proteasome containing the 20 S core and 19 S cap. Monomeric alpha- and beta-synucleins inhibited the 20 S and 26 S proteasomal activities only weakly, but monomeric gamma-synuclein strongly inhibited ubiquitin-independent proteolysis. The IC(50) of monomeric gamma-synuclein for the 20 S proteolysis was 400 nm. In monomeric form, none of the three synuclein proteins inhibited 26 S ubiquitin-dependent proteasomal activity. Although beta-synuclein had no direct effect on proteasomal activity, co-incubating monomeric beta-synuclein with aggregated alpha-synuclein antagonized the inhibition of the 26 S ubiquitin-independent proteasome by aggregated alpha-synuclein when added before the aggregated alpha-synuclein. Co-incubating beta-synuclein with gamma-synuclein had no effect on the inhibition of the 20 S proteasome by monomeric gamma-synuclein. Immunoprecipitation and pull-down experiments suggested that antagonism by beta-synuclein resulted from binding to alpha-synuclein rather than binding to S6'. Pull-down experiments demonstrated that recombinant monomeric beta-synuclein does not interact with the proteasomal subunit S6', unlike alpha-synuclein, but beta-synuclein does bind alpha-synuclein and competes with S6' for binding to alpha-synuclein. Based on these data, we hypothesize that the alpha- and gamma-synucleins regulate proteasomal function and that beta-synuclein acts as a negative regulator of alpha-synuclein.
Cancer Res. 2004 Jul 1;64(13):4539-46.
Source
North Shore Long Island Jewish Research Institute, Department of Radiation Oncology, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
Abstract
Synucleins are emerging as central players in the formation of pathologically insoluble deposits characteristic of neurodegenerative diseases. gamma synuclein (SNCG), previously identified as a breast cancer-specific gene (BCSG1), is also highly associated with breast or ovarian cancer progression. However, the molecular targets of SNCG aberrant expression in breast cancer have not been identified. Here, we demonstrated a chaperone activity of SNCG in the heat-shock protein (Hsp)-based multiprotein chaperone complex for stimulation of estrogen receptor (ER)-alpha signaling. As an ER-alpha-associated chaperone, SNCG participated in Hsp-ER-alpha complex, enhanced the high-affinity ligand-binding capacity of ER-alpha, and stimulated ligand-dependent activation of ER-alpha. The SNCG-mediated stimulation of ER-alpha transcriptional activity is consistent with its stimulation of mammary tumorigenesis in response to estrogen. These data indicate that SNCG is a new chaperone protein in the Hsp-based multiprotein chaperone complex for stimulation of ligand-dependent ER-alpha signaling and thus stimulates hormone-responsive mammary tumorigenesis.
J Neurochem. 2004 Jun;89(5):1126-36.
Source
Department of Preclinical Veterinary Sciences, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, Scotland, UK.
Abstract
The growing body of evidence suggests that intermediate products of alpha-synuclein aggregation cause death of sensitive populations of neurones, particularly dopaminergic neurones, which is a critical event in the development of Parkinson's disease and other synucleinopathies. The role of two other members of the family, beta-synuclein andgamma-synuclein, in neurodegeneration is less understood. We studied the effect of inactivation of gamma-synucleingene on mouse midbrain dopaminergic neurones. Reduced number of dopaminergic neurones was found in substantia nigra pars compacta (SNpc) but not in ventral tegmental area (VTA) of early post-natal and adult gamma-synuclein null mutant mice. Similar reductions were revealed in alpha-synuclein and double alpha-synuclein/gamma-synuclein null mutant animals. However, in none of these mutants did this lead to significant changes of striatal dopamine or dopamine metabolite levels and motor dysfunction. In all three studied types of null mutants, dopaminergic neurones of SNpc were resistant to methyl-phenyl-tetrahydropyridine (MPTP) toxicity. We propose that both synucleins are important for effective survival of SNpc neurones during critical period of development but, in the absence of these proteins, permanent activation of compensatory mechanisms allow many neurones to survive and become resistant to certain toxic insults.
Mol Cell Biol. 2003 Nov;23(22):8233-45.
Ninkina N, Papachroni K, Robertson DC, Schmidt O, Delaney L, O'Neill F, Court F, Rosenthal A, Fleetwood-Walker SM,Davies AM, Buchman VL.
Source
Department of Preclinical Veterinary Sciences, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, Scotland, U.K.
Abstract
Homologous recombination in ES cells was employed to generate mice with targeted deletion of the first three exons of the gamma-synuclein gene. Complete inactivation of gene expression in null mutant mice was confirmed on the mRNA and protein levels. Null mutant mice are viable, are fertile, and do not display evident phenotypical abnormalities. The effects of gamma-synuclein deficiency on motor and peripheral sensory neurons were studied by various methods in vivo and in vitro. These two types of neurons were selected because they both express high levels of gamma-synuclein from the early stages of mouse embryonic development but later in the development they display different patterns of intracellular compartmentalization of the protein. We found no difference in the number of neurons between wild-type and null mutant animals in several brain stem motor nuclei, in lumbar dorsal root ganglia, and in the trigeminal ganglion. The survival of gamma-synuclein-deficient trigeminal neurons in various culture conditions was not different from that of wild-type neurons. There was no difference in the numbers of myelinated and nonmyelinated fibers in the saphenous nerves of these animals, and sensory reflex thresholds were also intact in gamma-synuclein null mutant mice. Nerve injury led to similar changes in sensory function in wild-type and mutant mice. Taken together, our data suggest that like alpha-synuclein, gamma-synuclein is dispensable for the development and function of the nervous system.
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Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2003 Oct;20(5):444-6.
[Article in Chinese]
Source
Department of Neurology, Changhai Hospital, the Second Military Medical University, Shanghai, 200433 P R China. jjsulcg@yahoo.com
Abstract
OBJECTIVE:
To evaluate the relationship between idiopathic Parkinson's disease (PD) and two polymorphisms (C243G and A377T) of the gamma-synuclein gene in a Chinese Han population of Shanghai area.
METHODS:
Polymorphic genotyping was performed with PCR-RPLP technique. Association analysis was carried out in 145 unrelated idiopathic PD patients and 184 age-matched healthy controls.
RESULTS:
The authors failed to detect any distributional difference of the C243G and A377T polymorphisms of thegamma-synuclein gene between PD cases and control subjects, nor did they find any association.
CONCLUSION:
These data do not support that gamma-synuclein gene C243G and A377T polymorphisms are involved in idiopathic PD onset in the Han population of Shanghai area.
Cancer Epidemiol Biomarkers Prev. 2003 Sep;12(9):920-5.
Source
Department of Surgery, XinHua Hospital affiliated with Shanghai Second Medical University, Shanghai, China.
Abstract
Gamma-synuclein (SNCG), also referred as breast cancer-specific gene 1, is the third member of a neuronal protein family synuclein. SNCG is highly expressed in human-infiltrating breast carcinomas but not expressed in normal or benign breast tissues. To evaluate the clinical relevance of SNCG expression in breast cancer progression and its correlation with clinical parameters, we analyzed SNCG expression in 79 clinical breast specimens from primary breast cancer, hyperplasia, and fibroadenoma patients by reverse transcription-PCR. The status of estrogen receptor, progesterone receptor, proliferating cell nuclear antigen, and C-erBb2 was also analyzed by immunohistochemistry. Overall SNCG mRNA expression was detectable in 38.8% of breast cancers. However, 79% of stage III/IV breast cancers were positive for SNCG expression, whereas only 15% of stage I/II breast cancers were positive for SNCG expression. In contrast, the expression of SNCG was undetectable in all benign breast lesions. The expression of SNCG was strongly correlated to the stage of breast cancer (P=0.000). This study suggests that the expression of SNCG is stage specific for breast cancer. SNCG is expected to be a useful marker for breast cancer progression and a potential target for breast cancer treatment.
World J Gastroenterol. 2003 Sep;9(9):1900-3.
Source
Laboratory of Cell and Molecular Biology, Cancer Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.
Abstract
AIM:
To investigate gene expression pattern of human gamma-synuclein gene in human esophageal squamous cell carcinoma (ESCC) by using semi-quantitive reverse transcription polymerase chain reaction (RT-PCR), and to study the role of gamma-synuclein in the development of human ESCC.
METHODS:
Semi-quantitive RT-PCR of 27 pairs of specimens of human ESCC tissues and corresponding normal tissues was used to investigate the expression pattern of gamma-synuclein in ESCC. 9706/gamma-syn cells in whichgamma-synuclein was overexpressed were obtained through cloning gamma-synuclein gene by PCR and transfecting it into ESCC 9706 cells, then selecting with G-418 for 14 days. The biological effects of gamma-synuclein were measured and compared between 9706/gamma-syn and 9706/vec cells by cell growth curve and soft agar assay.
RESULTS:
RT-PCR showed that gamma-synuclein gene was expressed in all the 27 cases of normal epithelial tissues, while downregulation of gamma-synuclein was observed in 16 out of the 27 cases (59.3 %) of ESCC. There were also 6 cases of ESCC tissues with a high expression level of gamma-synuclein mRNA. In functional analysis we found that over-expression of gamma-synuclein in ESCC 9706 cells could inhibit the growth rate and transformation ability of ESCC 9706 cells.
CONCLUSION:
The low expression level of gamma-synuclein in human ESCC and the biological effects of gamma-synuclein over-expression on ESCC 9706 cells suggest that gamma-synuclein may play a role as a negative regulator in the development of human ESCC.
Cancer Res. 2003 Jul 15;63(14):3899-903.
Source
Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
Abstract
Synucleins are emerging as central player in the fundamental neural processes and in the formation of pathologically insoluble deposits characteristic of Alzheimer's disease and Parkinson's disease. However, gamma Synuclein (SNCG) is also highly associated with breast cancer and ovarian cancer progression. Whereas most studies of this group of proteins have been directed to the elucidation of their role in the formation of depositions in brain tissue, the normal cellular function of this highly conserved synuclein family remains largely unknown. A notable finding in this study is that SNCG, identified previously as a breast cancer-specific gene 1, strongly stimulated the ligand-dependent transcriptional activity of estrogen receptor-alpha (ER-alpha) in breast cancer cells. Augmentation of SNCG expression stimulated transcriptional activity of ER-alpha, whereas compromising endogenous SNCG expression suppressed ER-alpha signaling. The SNCG-stimulated ER-alpha signaling was demonstrated in three different cell systems including ER-alpha-positive and SNCG-negative MCF-7 cells, ER-alpha-positive and SNCG-positive T47D cells, and SNCG-negative and ER-alpha-negative MDA-MB-435 cells. The SNCG-mediated stimulation of ER-alpha transcriptional activity is consistent with its stimulation of the ligand-dependent cell growth. Whereas overexpression of SNCG stimulated the ligand-dependent cell proliferation, suppression of endogenous SNCG expression significantly inhibited cell growth in response to estrogen. The stimulatory effect of SNCG on ERalpha-regulated gene expression and cell growth can be effectively inhibited by antiestrogens. These data indicate that SNCG is required for efficient ER-alpha signaling and, thus, stimulated hormone-responsive mammary tumors.
Exp Neurol. 2003 Jul;182(1):195-207.
Source
NeuroRepair Group, University of Tasmania, 7000, Hobart, Tasmania, Australia.
Abstract
Genetic and protein studies have indicated abnormalities in alpha-synuclein in neurodegenerative diseases. However, the developmental localization and cellular role of synuclein isoforms is contentious. We investigated the cellular localization of alpha-, beta-, and gamma-synuclein in developing cultured rat neurons and following axonal transection of relatively mature neurons, a model that disrupts the axonal cytoskeleton and results in regenerative sprouting. Cortical neurons were grown up to 21 days in vitro (DIV). Axon bundles at 21 DIV were transected and cellular changes examined at 4 and 24 h post-injury. Immunohistochemistry demonstrated that alpha- and beta-synuclein were localized to cellular cytosol and growth cones at 3DIV, with accumulating puncta-like labeling within axons and growth cones by 10-21DIV. In contrast, gamma-synuclein immunoreactivity was limited at all time points. By 21DIV, alpha- and beta-synuclein were present in the same neurons but largely in separate subregions, only 26% of puncta contained both alpha- and beta-synuclein immunoreactivity. Less than 20% of alpha-, beta-, and pan-synuclein immunoreactive puncta directly colocalized to synaptophysin profiles at 10DIV, decreasing to 10% at 21DIV. Both alpha- and beta-synuclein accumulated substantially within damaged axons at 21DIV and were localized to cytoskeletal abnormalities. At latter time points post-injury, alpha- and beta-synuclein immunoreactive puncta were localized to growth cone-like structures in regenerating neurites. This study shows that alpha- and beta-synuclein have a precise localization within cortical neurons and are generally nonoverlapping in their distribution within individual neurons. In addition, synuclein proteins accumulate rapidly in damaged axons and may have a role in regenerative sprouting.
Acta Neuropathol. 2003 Aug;106(2):167-75. Epub 2003 May 28.
Source
Department of Pathology, University of Oklahoma Health Science Center (OUHSC), Rm 451, 940 Stanton L. Young Blvd., Oklahoma City, OK 73104, USA. KarMing-Fung@ouhsc.edu
Abstract
alpha-, beta- and gamma-synuclein are highly homologous proteins that are found predominantly in neurons. Abnormal accumulation of synucleins has been associated with diseases of the central nervous system particularly Parkinson's disease. Immunoreactivity of alpha-synuclein is demonstrated in brain tumors with neuronal differentiation and in schwannomas, whereas gamma-synuclein has been demonstrated in breast and ovarian carcinomas. The immunoreactivity of synucleins has not been described in glial tumors. Immunoreactivity of synucleins in glial cells in culture and in pathological conditions, however, suggests that synucleins may be expressed by glial tumors. We studied the expression of alpha-, beta-, and gamma-synuclein in 84 human brain tumors (24 ependymomas, 31 astrocytomas, 8 oligodendrogliomas, and 21 medulloblastomas) by immunohistochemistry. Our study demonstrates immunoreactivity for gamma-synuclein in high-grade glial tumors; immunoreactivity is found in all anaplastic ependymomas but in only 33% of ependymomas and 16% of myxopapillary ependymomas. Immunoreactivity for gamma-synuclein is noted in 63% of glioblastomas but not in other astrocytic tumors. Of medulloblastomas, 76% have immunoreactivity for either alpha- or beta-synuclein or both; no immunoreactivity for gamma-synuclein is seen in medulloblastomas.
Arch Biochem Biophys. 2003 Feb 1;410(1):167-76.
Source
Department of Molecular Biosciences, Kansas University, 4004 Haworth Hall, Lawrence, KS 66045, USA.
Abstract
gamma-Synuclein is a small cytoplasmic protein implicated in neurodegenerative diseases and cancer. However, the mechanism of its involvement in diseases is not clear. We studied the role of gamma-synuclein in the regulation of matrix metalloproteinases in retinoblastoma cell culture. Matrix metalloproteinases play important roles in the remodeling of extracellular matrix implicated in tumor progression and in the neurodegenerative diseases. Western blot and zymography data demonstrated a moderate elevation of matrix metalloproteinases-2 and significant upregulation of matrix metalloproteinases-9 in stable cell lines overexpressing gamma-synuclein. No effect of gamma-synucleinoverexpression on matrix metalloproteinases-1 level or activity was found. Chloramphenicol-acetyltransferase assay demonstrated that overexpression of gamma-synuclein increases the efficiency of the matrix metalloproteinases-9 promoter. This increment of promoter activity may be mediated by the AP-1 binding site(s), since point mutations in one of these sites (Pr18 or Pr19) and elimination of the distal AP-1 site (Pr14) reduced the increment of promoter activity.
J Biol Chem. 2002 Sep 20;277(38):35050-60. Epub 2002 Jul 16.
Source
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Abstract
Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma-synuclein over-expression can enhance tumorigenicity. In the current study, we have found thatgamma-synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1), and have shown that over-expression of gamma-synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of gamma-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that gamma-synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma-synuclein-expressing cells, indicating that the paclitaxel- or vinblastine-activated apoptosis pathway is blocked by gamma-synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and gamma-synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of gamma-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs.
J Neurosci Res. 2002 Apr 1;68(1):97-106.
Source
Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, Missouri, USA.
Abstract
Synucleins are small proteins associated with neurodegenerative diseases and some forms of cancer. They are studied predominantly in the brain; information about their presence and functions in ocular tissues is scarce. Here we describe the localization of three members of the synuclein family in the optic nerve of donors with different types of glaucoma compared with control samples from donors without ocular diseases. We did not find significant differences in the localization of alpha- and beta-synucleins in the optic nerve or retina of glaucoma patients compared with controls, whereas considerable redistribution of gamma-synuclein occurred in the glaucomatous optic nerve compared with control eye without glaucoma. In the optic nerve from control and glaucomatous individuals, nerve bundles are immunopositive for gamma-synuclein; however, a strong gamma-synuclein-immunopositive staining in a subset of glial cells was observed in the lamina and postlamina cribrosa regions of the optic nerve only in glaucoma patients. In the optic nerve of rats with episcleral vein cauterization used as an animal model of glaucoma, the quantity of both gamma-synuclein mRNA and protein was decreased compared with the optic nerves of control animals. Incubation of rat astrocyte culture at elevated hydrostatic pressure reduced the amount of gamma-synuclein but did not affect the quantities of actin and glial fibrillary acidic protein. These data suggest that significant changes in the pattern of expression and/or localization occur in the glaucomatous optic nerve for gamma-synuclein but not for alpha- and beta-members of the synuclein family.
Copyright 2002 Wiley-Liss, Inc.
Cell Motil Cytoskeleton. 2001 Aug;49(4):218-28.
Source
Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, Missouri 63110, USA. surguchov@vision.wustl.edu
Abstract
Synucleins are small, highly conserved proteins in vertebrates, especially abundant in neurons and typically enriched in presynaptic terminals. alpha-Synuclein protein and a fragment of it, called NAC, have been found in association with pathological lesions of neurodegenerative diseases. Recently, mutations in a alpha-synuclein gene have been reported in families susceptible to an inherited form of Parkinson's diseases. In addition, alpha-synuclein has been implicated in the pathophysiology of other neurodegenerative diseases, including Alzheimer's disease and multiple system atrophy. Far less is known about other members of the synuclein family, beta- and gamma-synucleins. gamma-synuclein is up-regulated in several types of cancer and may affect the integrity of the neurofilament network, while its bovine ortholog, synoretin, activates the Elk-1 signal transduction pathway. In this paper, we present data about the localization and properties of human and bovine gamma-synuclein in several neuronal and non-neuronal cell cultures derived from ocular tissues. We show that gamma-synuclein is present in the perinuclear area and is localized to centrosomes in several types of human interphase cells and in bovine retinal pigment epithelium. In mitotic cells, gamma-synucleinstaining is localized to the poles of the spindle. Further, overexpression of synoretin in retinoblastoma cells up-regulates MAPK and Elk-1. These results support the view that gamma-synuclein is a centrosome protein that may be involved in signal transduction pathways.
Copyright 2001 Wiley-Liss, Inc.
Neurosci Lett. 2001 Sep 14;310(2-3):191-3.
Source
Department of Neurology, Ruhr-University, St. Josef-Hospital, Bochum, Germany. rejko.krueger@unit_tuebingen.de
Abstract
Mutations in the alpha-synuclein gene are responsible for an autosomal-dominantly inherited form of Parkinson's disease (PD) and alpha-synuclein was found to be the major component of Lewy bodies in PD. Because of the high homology to alpha-synuclein and the abundance in neuronal tissues, we investigated the gamma-synuclein gene in PD. We analyzed 262 German PD patients and 179 healthy German controls via two polymorphisms in the gamma-synucleingene. No significant differences in the allelic or genotypic distributions of the investigated polymorphisms were observed between patients and controls. In addition no evidence for an increased risk of combined genotypes of polymorphisms in the gamma-synuclein and the alpha-synuclein gene was found. Therefore, our results do not support a major role of thegamma-synuclein gene in PD.
Exp Neurol. 2001 Apr;168(2):347-55.
Source
Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Abstract
Although the functions of alpha-, beta-, and gamma-synuclein (alphaS, betaS, gammaS, respectively) are unknown, these synaptic proteins are implicated in the pathogenesis of Parkinson's disease (PD) and related disorders. For example, alphaS forms Lewy bodies (LBs) in substantia nigra (SN) neurons of PD. However, since it is not known how these hallmark PD lesions contribute to the degeneration of SN neurons or what the normal function of alphaS is in SN neurons, we studied the developing human SN from 11 weeks gestational age (GA) to 16 years of age using immunohistochemistry and antibodies to alphaS, betaS, gammaS, other synaptic proteins, and tyrosine hydoxylase (TH). SN neurons expressed TH at 11 weeks GA and alphaS, betaS, and gammaS appeared initially at 15, 17, and 18 weeks GA, respectively. These synucleins first appeared in perikarya of SN neurons after synaptophysin, but about the same time as synaptotagmin and synaptobrevin. Redistribution of alphaS from perikarya to processes of SN neurons occurred by 18 weeks GA in parallel with synaptophysin, while betaS and synaptotagmin were redistributed similarly between 20 and 28 weeks GA and this also occurred with gammaS and synaptobrevin between 33 weeks GA and 9 months postnatal. These data suggest that alphaS, betaS, and gammaS may play a functional role in the development and maturation of SN neurons, but it remains to be determined how sequestration of alphaS as LBs in PD contributes to the degeneration of SN neurons.
J Biol Chem. 2000 Nov 3;275(44):34574-9.
Biere AL, Wood SJ, Wypych J, Steavenson S, Jiang Y, Anafi D, Jacobsen FW, Jarosinski MA, Wu GM, Louis JC, Martin F,Narhi LO, Citron M.
Source
Amgen, Inc., Thousand Oaks, California 91320-1789, USA. abiere@amgen.com
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies. Recently, two point mutations in alpha-synuclein were found to be associated with familial PD, but as of yet no mutations have been described in the homologous genes beta- and gamma-synuclein. alpha-Synuclein forms the major fibrillar component of Lewy bodies, but these do not stain for beta- or gamma-synuclein. This result is very surprising, given the extent of sequence conservation and the high similarity in expression and subcellular localization, in particular between alpha- and beta-synuclein. Here we compare in vitro fibrillogenesis of all three purified synucleins. We show that fresh solutions of alpha-, beta-, and gamma- synuclein show the same natively unfolded structure. While over time alpha-synuclein forms the previously described fibrils, no fibrils could be detected for beta- andgamma-synuclein under the same conditions. Most importantly, beta- and gamma-synuclein could not be cross-seeded with alpha-synuclein fibrils. However, under conditions that drastically accelerate aggregation, gamma-synuclein can form fibrils with a lag phase roughly three times longer than alpha-synuclein. These results indicate that beta- andgamma-synuclein are intrinsically less fibrillogenic than alpha-synuclein and cannot form mixed fibrils with alpha-synuclein, which may explain why they do not appear in the pathological hallmarks of PD, although they are closely related to alpha-synuclein and are also abundant in brain.
Am J Pathol. 2000 Aug;157(2):361-8.
Source
Department of Neurology, Medical College of Pennsylvania Hahnemann University. the Center for Neurodegenerative Disease Research, and the Department of Neurology, the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract
Neurodegeneration with brain iron accumulation, type 1 (NBIA 1), or Hallervorden-Spatz syndrome, is a rare neurodegenerative disorder characterized clinically by Parkinsonism, cognitive impairment, pseudobulbar features, as well as cerebellar ataxia, and neuropathologically by neuronal loss, gliosis, and iron deposition in the globus pallidus, red nucleus, and substantia nigra. The hallmark pathological lesions of NBIA 1 are axonal spheroids, but Lewy body (LB)-like intraneuronal inclusions, glial inclusions, and rare neurofibrillary tangles also occur. Here we show that there is an accumulation of alpha-synuclein (alphaS) in LB-like inclusions, glial inclusions, and spheroids in the brains of three NBIA 1 patients. Further, beta-synuclein (betaS) and gamma-synuclein (gammaS) immunoreactivity was detected in spheroids but not in LB-like or glial inclusions. Western blot analysis demonstrated high-molecular weight alphaS aggregates in the high-salt-soluble and Triton X-100-insoluble/sodium dodecyl sulfate-soluble fraction of the NBIA 1 brain. Significantly, the levels of alphaS were markedly reduced in the Triton X-100-soluble fractions compared to control brain, and unlike other synucleinopathies, insoluble alphaS did not accumulate in the formic acid-soluble fraction. These findings expand the concept of neurodegenerative synucleinopathies by implicating alphaS, betaS, and gammaS in the pathogenesis of NBIA 1.
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13450-5.
Source
Department of Neurology, Medical College of Pennsylvania, Hahnemann University, 245 North 15th Street, Philadelphia, PA 19129, USA.
Abstract
Pathogenic alpha-synuclein (alphaS) gene mutations occur in rare familial Parkinson's disease (PD) kindreds, and wild-type alphaS is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease, but beta-synuclein (betaS) and gamma-synuclein (gammaS) have not yet been implicated in neurological disorders. Here we show that in PD and DLB, but not normal brains, antibodies to alphaS and betaS reveal novel presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2/3 regions, whereas antibodies to gammaS detect previously unrecognized axonal spheroid-like lesions in the hippocampal dentate molecular layer. The aggregation of other synaptic proteins and synaptic vesicle-like structures in the alphaS- and betaS-labeled hilar dystrophic neurites suggests that synaptic dysfunction may result from these lesions. Our findings broaden the concept of neurodegenerative "synucleinopathies" by implicating betaS and gammaS, in addition to alphaS, in the onset/progression of PD and DLB.
Neurosci Lett. 1999 Feb 19;261(3):186-8.
Source
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA.
Abstract
Alzheimer's disease (AD) is a complex disease with the possible involvement of several genes. Genetic studies on sporadic late-onset AD have determined APOE*4 to be the major risk factor. Members of the synuclein gene family are potential candidates for the risk of AD. The persyn gene (gamma-synuclein) has recently been characterized and a common polymorphism (Glu110Val) has been identified. In this study we investigated the association of this polymorphism with sporadic late-onset AD patients. We screened DNA samples of 313 late-onset cases and 352 controls. No significant association was observed between the missense mutation and AD. When the data were stratified by APOE*4 carriers and non-APOE*4 carriers, no difference was seen for the Glu110Val polymorphism. There was also no difference in genotype or allele frequency when stratified by the ACT*A allele. Although our data show no effect of this persyn polymorphism in AD, characterization of additional polymorphisms in this gene may provide more conclusive answers.
DNA Res. 1998 Dec 31;5(6):401-2.
Lavedan C, Buchholtz S, Auburger G, Albin RL, Athanassiadou A, Blancato J, Burguera JA, Ferrell RE, Kostic V, Leroy E,Leube B, Mota-Vieira L, Papapetropoulos T, Pericak-Vance MA, Pinkus J, Scott WK, Ulm G, Vasconcelos J, Vilchez JJ,Nussbaum RL, Polymeropoulos MH.
Source
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. lavedan@nhgri.nih.gov
Hum Genet. 1998 Jul;103(1):106-12.
Source
Laboratory of Genetic Disease Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract
We have identified and characterized a new member of the human synuclein gene family, gamma-synuclein (SNCG). This gene is composed of five exons, which encode a 127 amino acid protein that is highly homologous to alpha-synuclein, which is mutated in some Parkinson's disease families, and to beta-synuclein. The gamma-synuclein gene is localized to chromosome 10q23 and is principally expressed in the brain, particularly in the substantia nigra. We have determined its genomic sequence, and established conditions for sequence analysis of each of the exons. The gamma-synuclein gene, also known as BCSG1, was recently found to be overexpressed in advanced infiltrating carcinoma of the breast. Our survey of the EST database indicated that it might also be overexpressed in an ovarian tumor.
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