Friday, January 6, 2012

hyperphosphorylation| What is hyperphosphorylation|Papers on hyperphosphorylation |Research on hyperphosphorylation | Publications on hyperphosphor


1.
Amyotroph Lateral Scler. 2012 Jan 3. [Epub ahead of print]

Widespread neuronal and glial hyperphosphorylated tau deposition in ALS with cognitive impairment.

Source

Robarts Research Institute, The University of Western Ontario.

Abstract

Although the biological basis of frontotemporal syndromes associated with amyotrophic lateral sclerosis (ALS) is considered to be altered metabolism of TDP-43, in ALS with cognitive impairment (ALSci) the metabolism of tau protein is also altered. This includes neuronal hyperphosphorylation (pThr(175)). Using novel polyclonal phospho-tau antibodies (pSer(208, 210), pThr(217) and pThr(175)) and antibodies directed against PHF tau (pSer(202)), TDP-43 or ubiquitin, we characterized tau deposition in ALS and ALSci. In ALS, we observed pThr(175) tau immunoreactive intraneuronal and neuritic aggregates throughout the amygdala and entorhinal cortex. In ALSci, this extended to the anterior cingulate gyrus, superior frontal cortex and substantia nigra. The pThr(217) antibody detected widespread astrocytic tau deposition, including punctuate or fibrillary aggregates, or intensely immunoreactive tufted astrocytes in the superior frontal cortex, anterior cingulate gyrus, entorhinal cortex, amygdala and basal ganglia of ALS. In ALSci, a similar but more widely distributed pThr(217) pathology was observed. There was no correlation between the extent of pathological tau deposition and TDP-43 pathology, although nuclear TDP-43 immunoreactivity was absent in neurons with tau pathology. In conclusion, ALSci is unique in possessing both tau and TDP-43 pathology. The presence of widespread astrocytic tau pathology suggests that ALSci may initially be characterized by astrocytic pathology.

PMID:
22214313
[PubMed - as supplied by publisher]
2.
Int Immunol. 2011 Dec 29. [Epub ahead of print]

Fine-tuning of proximal TCR signaling by ZAP-70 tyrosine residues in Jurkat cells.

Source

Department of Immunology and Biotechnology, University of Pecs, H-7643 Pecs, Hungary.

Abstract

Zeta-chain-associated protein kinase of 70kDa (ZAP-70) kinase is a key regulator in the early steps of TCR signaling but some aspects of its fine regulation are still unclear. From its 31 tyrosine (Y) residues, 11 phosphorylation sites have been identified, some with activator (Y315 and Y493) or inhibitory (Y292 and Y492) and others with unknown function (Y069, Y126 and Y178). In our present work, we aimed to elucidate the role of different Y residues of ZAP-70, especially those with unknown function, in calcium signaling and the autoregulation of the kinase. ZAP-70-deficient Jurkat cells (P116) were stably reconstituted with point-mutated ZAP-70 constructs where tyrosine residues 069, 126, 178, 238, 292, 315, 492 or 493 were replaced with phenylalanine (F). The anti-CD3-elicited calcium signal increased in F069-, F292- and F492-ZAP-70-expressing cell lines but decreased in the F126-, F315- and F493-ZAP-70-expressing cell lines. ZAP-70 point mutations led to phosphorylation changes predominantly in SH2 domain containing leukocyte protein of 76kDa (SLP-76) but not linker of activated T cells (LAT) during CD3-activation; moreover, we detected basalhyperphosphorylation of SLP-76 Y128 in the F126-, F178- and F492-ZAP-70-expressing cell lines. In summary, Y069, Y178, Y292 and Y492 have inhibitory, while Y126, Y315 and Y493 activator role in anti-CD3-induced T-cell activation. Phosphorylation changes in LAT and SLP-76 suggest that fine regulation of ZAP-70 on calcium signaling is rather transmitted through SLP-76 not LAT. Additionally, negative or positive autoregulatory function of Y292 and Y493 or Y315, respectively, was revealed in ZAP-70. These data indicate that previously not characterized Y069, Y126 and Y178 in ZAP-70 participate in the fine regulation of TCR signaling.

PMID:
22207134
[PubMed - as supplied by publisher]
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3.
Mol Pharm. 2011 Dec 29. [Epub ahead of print]

Phosphorus Dendrimers Affect Alzheimer's (Aβ1-28) Peptide and MAP-Tau Protein Aggregation.

Abstract

Alzheimer's disease (AD) is characterized by pathological aggregation of β-amyloid peptides and MAP-Tau protein. β-amyloid (Aβ) is a peptide responsible for extracellular Alzheimer's plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of Aβ are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (Aβ1-28) and MAP-Tau protein. We have demonstrated that CPDs are able to affect β-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the Aβ1-28 aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimer's disease.

PMID:
22206488
[PubMed - as supplied by publisher]
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4.
Front Biosci (Elite Ed). 2012 Jan 1;4:1582-605.

Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease.

Source

Departments of Neurology, Neurosurgery, and Neuropathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI.

Abstract

Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.

PMID:
22201977
[PubMed - in process]
5.
PLoS One. 2011;6(12):e29248. Epub 2011 Dec 14.

STAT1 Hyperphosphorylation and Defective IL12R/IL23R Signaling Underlie Defective Immunity in Autosomal Dominant Chronic Mucocutaneous Candidiasis.

Source

Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Abstract

We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency.

PMID:
22195034
[PubMed - in process]
PMCID: PMC3237610
Free PMC Article
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6.
Cell Death Differ. 2011 Dec 23. doi: 10.1038/cdd.2011.188. [Epub ahead of print]

WW domain-containing oxidoreductase promotes neuronal differentiation via negative regulation of glycogen synthase kinase 3β

Source

Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.

Abstract

WW domain-containing oxidoreductase (WWOX), a putative tumour suppressor, is suggested to be involved in thehyperphosphorylation of Alzheimer's Tau. Tau is a microtubule-associated protein that has an important role in microtubule assembly and stability. Glycogen synthase kinase 3β (GSK3β) has a vital role in Tau hyperphosphorylationat its microtubule-binding domains. Hyperphosphorylated Tau has a low affinity for microtubules, thus disrupting microtubule stability. Bioinformatics analysis indicated that WWOX contains two potential GSK3β-binding FXXXLI/VXRLE motifs. Immunofluorescence, immunoprecipitation and molecular modelling showed that WWOX interacts physically with GSK3β. We demonstrated biochemically that WWOX can bind directly to GSK3β through its short-chain alcohol dehydrogenase/reductase domain. Moreover, the overexpression of WWOX inhibited GSK3β-stimulated S396 and S404 phosphorylation within the microtubule domains of Tau, indicating that WWOX is involved in regulating GSK3β activity in cells. WWOX repressed GSK3β activity, restored the microtubule assembly activity of Tau and promoted neurite outgrowth in SH-SY5Y cells. Conversely, RNAi-mediated knockdown of WWOX in retinoic acid (RA)-differentiated SH-SY5Y cells inhibited neurite outgrowth. These results suggest that WWOX is likely to be involved in regulating GSK3β activity, reducing the level of phosphorylated Tau, and subsequently promoting neurite outgrowth during neuron differentiation. In summary, our data reveal a novel mechanism by which WWOX promotes neuronal differentiation in response to RA.Cell Death and Differentiation advance online publication, 23 December 2011; doi:10.1038/cdd.2011.188.

PMID:
22193544
[PubMed - as supplied by publisher]
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7.
J Biol Chem. 2011 Dec 19. [Epub ahead of print]

Propyl isomerase Pin1 promotes APP protein turnover by inhibiting GSK3β kinase activity: A novel mechanism for Pin1 to protect against Alzheimer's disease.

Source

Beth Israel Deaconese Medical Center, United States;

Abstract

Alzheimer's disease (AD) is characterized by the presence of senile plaques of amyloid-beta peptides (Aβ) derived from amyloid precursor protein (APP) and neurofibrillary tangles composed of hyperphosphorylated tau. Increasing APP gene dosage or expression has been shown to cause familial early-onset AD. However, whether protein stability of APP is regulated is unclear. The prolyl isomerase Pin1 and glycogen synthase 3β (GSK3β) have been shown to have the opposite effects on APP processing and tau hyperphosphorylation, relevant to the pathogenesis of AD. However, nothing is known about their relationship. In this study, we found that Pin1 binds to the pT330-P motif in GSK3β to inhibit its kinase activity. Furthermore, Pin1 promotes protein turnover of APP by inhibiting GSK3β activity. A point mutation either at T330, the Pin1-binding site in GSK3β, or T668, the GSK3β phosphorylation site in APP, abolished the regulation of GSK3β activity, T668 phosphorylation and APP stability by Pin1, resulting in reduced non-amyloidogenic APP processing and increased APP levels. These results uncover a novel role of Pin1 in inhibiting GSK3β kinase activity to reduce APP protein levels, providing a previously unrecognized mechanism by which Pin1 protects against Alzheimer's disease.

PMID:
22184106
[PubMed - as supplied by publisher]
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8.
Neurobiol Dis. 2011 Dec 11. [Epub ahead of print]

Targeting hyperphosphorylated tau with sodium selenate suppresses seizures in rodent models.

Source

Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.

Abstract

Tau hyperphosphorylation has been implicated in the pathogenesis of a variety of forms of human epilepsy. Here we investigated whether treatment with sodium selenate, a drug which reduces pathological hyperphosphorylated tau by enhancement of PP2A activity, would inhibit seizures in rodent models. In vitro, sodium selenate reduced tau phosphorylation in human neuroblastoma cells and reversed the increase in tau phosphorylation induced by the PP2A inhibitor, okadaic acid. Sodium selenate treatment was then tested against three different rodent seizure models. Firstly the propensity of 6-Hz electrical corneal stimulation to induce seizures in adult mice was assessed following acute treatment with different doses of sodium selenate. Secondly, the number of seizures induced by pentylenetetrazole (PTZ) was quantified in rats following chronic sodium selenate treatment via drinking water. Finally, amygdala kindled rats were chronically treated with sodium selenate in drinking water and the length and the severity of the seizures evoked by stimulation of the amygdala recorded. The results demonstrated a dose-dependent protection of sodium selenate against 6-Hz stimulation induced seizures, and significant reduction in the total number of seizures following PTZ injection. Amygdala kindled rats chronically treated with sodium selenate had significantly shorter seizure duration compared controls, with more pronounced effects observed as the duration of treatment increased. The results of this study indicate that targeting hyperphosphorylated tau by treatment with sodium selenate has anti-seizure effects in a broad range of rodent models, and may represent a novel approach to treatment of patients with epilepsy.

Copyright © 2011. Published by Elsevier Inc.

PMID:
22182692
[PubMed - as supplied by publisher]
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9.
Biochem Biophys Res Commun. 2011 Dec 8. [Epub ahead of print]

The stress granule protein Vgl1 and poly(A)-binding protein Pab1 are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe.

Source

Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae 3-4-1, Higashi-Osaka 577-8502, Japan.

Abstract

Doxorubicin is an anthracycline antibiotic widely used for chemotherapy. Although doxorubicin is effective in the treatment of several cancers, including solid tumors and leukemias, the basis of its mechanism of action is not completely understood. Here, we describe the effects of doxorubicin and its relationship with stress granules formation in the fission yeast, Schizosaccharomyces pombe. We show that disruption of genes encoding the components of stress granules, including vgl1(+), which encodes a multi-KH type RNA-binding protein, and pab1(+), which encodes a poly(A)-binding protein, resulted in greater sensitivity to doxorubicin than seen in wild-type cells. Disruption of the vgl1(+) and pab1(+) genes did not confer sensitivity to other anti-cancer drugs such as cisplatin, 5-fluorouracil, and paclitaxel. We also showed that doxorubicin treatment promoted stress granule formation when combined with heat shock. Notably, doxorubicin treatment did not induce hyperphosphorylation of eIF2α, suggesting that doxorubicin is involved in stress granule assembly independent of eIF2α phosphorylation. Our results demonstrate the usefulness of fission yeast for elucidating the molecular targets of doxorubicin toxicity and suggest a novel drug-resistance mechanism involving stress granule assembly.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22172946
[PubMed - as supplied by publisher]
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10.
Cancer Cell. 2011 Dec 13;20(6):768-80.

WT1 Mutants Reveal SRPK1 to Be a Downstream Angiogenesis Target by Altering VEGF Splicing.

Source

Centre for Research in Biomedicine, Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, UK; Microvascular Research Laboratories, Bristol Heart Institute, School of Physiology and Pharmacology, University of Bristol, Preclinical Veterinary Sciences Building, Southwell Street, Bristol BS2 8EJ, UK.

Abstract

Angiogenesis is regulated by the balance of proangiogenic VEGF(165) and antiangiogenic VEGF(165)b splice isoforms. Mutations in WT1, the Wilms' tumor suppressor gene, suppress VEGF(165)b and cause abnormal gonadogenesis, renal failure, and Wilms' tumors. In WT1 mutant cells, reduced VEGF(165)b was due to lack of WT1-mediated transcriptional repression of the splicing-factor kinase SRPK1. WT1 bound to the SRPK1 promoter, and repressed expression through a specific WT1 binding site. In WT1 mutant cells SRPK1-mediated hyperphosphorylation of the oncogenic RNA binding protein SRSF1 regulated splicing of VEGF and rendered WT1 mutant cells proangiogenic. Altered VEGF splicing was reversed by wild-type WT1, knockdown of SRSF1, or SRPK1 and inhibition of SRPK1, which prevented in vitro and in vivo angiogenesis and associated tumor growth.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22172722
[PubMed - in process]
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11.
PLoS One. 2011;6(12):e28324. Epub 2011 Dec 6.

MicroRNA-1 and -133 Increase Arrhythmogenesis in Heart Failure by Dissociating Phosphatase Activity from RyR2 Complex.

Source

The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.

Abstract

In heart failure (HF), arrhythmogenic spontaneous sarcoplasmic reticulum (SR) Ca(2+) release and afterdepolarizations in cardiac myocytes have been linked to abnormally high activity of ryanodine receptors (RyR2s) associated with enhanced phosphorylation of the channel. However, the specific molecular mechanisms underlying RyR2hyperphosphorylation in HF remain poorly understood. The objective of the current study was to test the hypothesis that the enhanced expression of muscle-specific microRNAs (miRNAs) underlies the HF-related alterations in RyR2 phosphorylation in ventricular myocytes by targeting phosphatase activity localized to the RyR2. We studied hearts isolated from canines with chronic HF exhibiting increased left ventricular (LV) dimensions and decreased LV contractility. qRT-PCR revealed that the levels of miR-1 and miR-133, the most abundant muscle-specific miRNAs, were significantly increased in HF myocytes compared with controls (2- and 1.6-fold, respectively). Western blot analyses demonstrated that expression levels of the protein phosphatase 2A (PP2A) catalytic and regulatory subunits, which are putative targets of miR-133 and miR-1, were decreased in HF cells. PP2A catalytic subunit mRNAs were validated as targets of miR-133 by using luciferase reporter assays. Pharmacological inhibition of phosphatase activity increased the frequency of diastolic Ca(2+) waves and afterdepolarizations in control myocytes. The decreased PP2A activity observed in HF was accompanied by enhanced Ca(2+)/calmodulin-dependent protein kinase (CaMKII)-mediated phosphorylation of RyR2 at sites Ser-2814 and Ser-2030 and increased frequency of diastolic Ca(2+) waves and afterdepolarizations in HF myocytes compared with controls. In HF myocytes, CaMKII inhibitory peptide normalized the frequency of pro-arrhythmic spontaneous diastolic Ca(2+) waves. These findings suggest that altered levels of major muscle-specific miRNAs contribute to abnormal RyR2 function in HF by depressing phosphatase activity localized to the channel, which in turn, leads to the excessive phosphorylation of RyR2s, abnormal Ca(2+) cycling, and increased propensity to arrhythmogenesis.

PMID:
22163007
[PubMed - in process]
PMCID: PMC3232211
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12.
Hum Mol Genet. 2011 Dec 19. [Epub ahead of print]

A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.

Source

Department of Pathology.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia in the elderly. Accumulating evidence supports soluble amyloid-β (Aβ) oligomers as the leading candidate for the causative agent in AD and synapses as the primary site of Aβ oligomer action. However, the molecular and cellular mechanisms by which Aβ oligomers cause synaptic dysfunction and cognitive impairments remain poorly understood. Using primary cultures of rat hippocampal neurons as a model system, we show that the partitioning defective-1 (PAR-1)/microtubule affinity-regulating kinase (MARK) family kinases act as critical mediators of Aβ toxicity on synapses and dendritic spines. Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after Aβ treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or Aβ treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. Our results reveal a critical role for PAR-1/MARK kinases in AD pathogenesis and suggest PAR-1/MARK inhibitors as potential therapeutics for AD and possibly other tauopathies where aberrant tau hyperphosphorylation is involved.

PMID:
22156579
[PubMed - as supplied by publisher]
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13.
Cell Res. 2011 Dec 6. doi: 10.1038/cr.2011.194. [Epub ahead of print]

Defective heart development in hypomorphic LSD1 mice.

Source

1] Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA [2] Epigenetics Program, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.

Abstract

Lysine-specific demethylase 1 (LSD1/AOF2/KDM1A), the first enzyme with specific lysine demethylase activity to be described, demethylates histone and non-histone proteins and is essential for mouse embryogenesis. LSD1 interacts with numerous proteins through several different domains, most notably the tower domain, an extended helical structure that protrudes from the core of the protein. While there is evidence that LSD1-interacting proteins regulate the activity and specificity of LSD1, the significance and roles of such interactions in developmental processes remain largely unknown. Here we describe a hypomorphic LSD1 allele that contains two point mutations in the tower domain, resulting in a protein with reduced interaction with known binding partners and decreased enzymatic activity. Mice homozygous for this allele die perinatally due to heart defects, with the majority of animals suffering from ventricular septal defects. Transcriptional profiling revealed altered expression of a limited subset of genes in the hearts. This includes an increase in calmodulin kinase (CK) 2β, the regulatory subunit of the CK2 kinase, which correlates with E-cadherinhyperphosphorylation. These results identify a previously unknown role for LSD1 in heart development, perhaps partly through the control of E-cadherin phosphorylation.Cell Research advance online publication 6 December 2011; doi:10.1038/cr.2011.194.

PMID:
22143567
[PubMed - as supplied by publisher]
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14.
J Bioenerg Biomembr. 2011 Dec;43(6):747-56. Epub 2011 Nov 30.

Cardioprotective effect of propranolol on diabetes-induced altered intracellular Ca(2+) signaling in rat.

Source

Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.

Abstract

We have previously shown that chronic treatment with propranolol had beneficial effects on heart function in rats during increasing-age in a gender-dependent manner. Herein, we hypothesize that propranolol would improve cardiac function in diabetic cardiomyopathy and investigated the benefits of chronic oral administration of propranolol on the parameters of Ca(2+) signaling in the heart of streptozotocin-diabetic rats. Male diabetic rats received propranolol (25 mg/kg, daily) for 12 weeks, 1 week after diabetes induction. Treatment of the diabetic rats with propranolol did not produce a hypoglycaemic effect whereas it attenuated the increased cell size. Basal and β-agonist response levels of left ventricular developed pressure were significantly higher in propranolol-treated diabetic rats relative to untreated diabetics while left ventricular end diastolic pressure of the treated diabetics was comparable to the controls. Propranolol treatment normalized also the prolongation of the action potential in papillary muscles from the diabetic rat hearts. This treatment attenuated the parameters of Ca(2+) transients, depressed Ca(2+) loading of the sarcoplasmic reticulum, and of the basal intracellular Ca(2+) level of diabetic cardiomyocytes. Furthermore, Western blot data indicated that the diabetes-induced alterations in the cardiac ryanodine receptor Ca(2+) release channel's hyperphosphorylation decreased the FKBP12.6 protein level. Also, the high phosphorylated levels of PKA and CaMKII were prevented with propranolol treatment. Chronic treatment with propranolol seems to prevent diabetes-related changes in heart function by controlling intracellular Ca(2+) signaling and preventing the development of left ventricular remodeling in diabetic cardiomyopathy.

PMID:
22127436
[PubMed - in process]
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15.
Exp Neurol. 2011 Nov 13. [Epub ahead of print]

Signaling mechanisms downstream of quinolinic acid targeting the cytoskeleton of rat striatal neurons and astrocytes.

Abstract

The studies of signaling mechanisms involved in the disruption of the cytoskeleton homeostasis were performed in a model of quinolinic acid (QUIN) neurotoxicity in vitro. This investigation focused on the phosphorylation level of intermediate filament (IF) subunits of astrocytes (glial fibrillary acidic protein - GFAP) and neurons (low, medium and high molecular weight neurofilament subunits - NFL, NFM and NFH, respectively). The activity of the phosphorylating system associated with the IFs was investigated in striatal slices of rat exposed to QUIN or treated simultaneously with QUIN plus glutamate receptor antagonists, calcium channel blockers or kinase inhibitors. Results showed that in astrocytes, the action of 100μM QUIN was mainly due to increased Ca(2+) influx through NMDA and L-type voltage-dependent Ca(2+) channels (L-VDCC). In neuronal cells QUIN acted through metabotropic glutamate receptor (mGluR) activation and influx of Ca(2+) through NMDA receptors and L-VDCC, as well as Ca(2+) release from intracellular stores. These mechanisms then set off a cascade of events including activation of PKA, PKCaMII and PKC, which phosphorylate head domain sites on GFAP and NFL. Also, Cdk5 was activated downstream of mGluR5, phosphorylating the KSP repeats on NFM and NFH. mGluR1 was upstream of phospholipase C (PLC) which, in turn, produced diacylglycerol (DAG) and inositol 3,4,5 triphosphate (IP3). DAG is important to activate PKC and phosphorylate NFL, while IP(3) contributed to Ca(2+) release from internal stores promoting hyperphosphorylation of KSP repeats on the tail domain of NFM and NFH. The present study supports the concept of glutamate and Ca(2+) contribution in excitotoxic neuronal damage provoked by QUIN associated to dysfunction of the cytoskeleton homeostasis and highlights the differential signaling mechanisms elicited in striatal astrocytes and neurons.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22116044
[PubMed - as supplied by publisher]
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16.
Eur J Pharmacol. 2011 Nov 12. [Epub ahead of print]

(Val(8)) glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains.

Source

Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, PR China.

Abstract

It has being shown that glucagon-like peptide-1 (GLP-1), a new anti-diabetes agent, significantly attenuated beta-amyloid (Aβ) levels in rats. In the present study, (Val(8))GLP-1 was used to prevent impairments in memory formation, tau hyperphosphorylation and ultra-structural changes induced by streptozotocin intracerebroventricular (i.c.v.) injection. A spatial water maze task was used to test the rats' learning and memory formation, Western blot was used to measure tau hyperphosphorylation/total tau, and transmission electron microscope was used to find ultra-structural changes. The results shown that streptozotocin induced a series of Alzheimer disease -like changes in behaviour, a significant decline in learning and memory formation, an increased expression of total tau and an increased ratio of phosphorylated tau, and damage to nucleus and nucleolus as seen in electron micrographs. After treatment with (Val(8))GLP-1 (50μM in 10μl i.c.v.), there is a significant improvement in learning and memory, a reduction in total tau expression and hyperphosphorylated tau levels, and a recovery of damaged cell nuclei and nucleolus. Our results indicated that (Val(8))GLP-1 might prevent age-related neurodegenerative changes by preventing decline of learning and memory formation, reduction of phosphorylated tau levels and protection of subcellular structures and morphology of neurons. Therefore, (Val(8))GLP-1 is potentially a novel treatment for Alzheimer's disease.

Copyright © 2011. Published by Elsevier B.V.

PMID:
22115895
[PubMed - as supplied by publisher]
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17.
Yeast. 2011 Oct 25. doi: 10.1002/yea.1915. [Epub ahead of print]

Activity of the yeast zinc-finger transcription factor War1 is lost with alanine mutation of two putative phosphorylation sites in the activation domain.

Source

Department of Molecular Biology and Biotechnology, University of Sheffield, UK.

Abstract

Saccharomyces cerevisiae acquires its resistance to carboxylate weak organic acids by inducing a plasma membrane ABC transporter, Pdr12. These acids activate a Zn(II)2Cys6 zinc-finger transcription factor, War1, which in turn induces thePDR12 gene. Mutation of the four potential sites of serine/threonine phosphorylation within the War1 activation domain revealed that Pdr12 induction was lost with mutations S923A or S930A, but not with the corresponding phosphomimetic mutations S923D or S930D. However, phosphorylation at these two sites has not been detected by mass spectrometry, so it still remains uncertain whether these are true sites of phosphorylation or merely serines whose side-chain hydroxyls are necessary for the proper structuring of the War1 activation domain. Mutation S923A prevented the sorbate-induced hyperphosphorylation of War1, while S930A caused War1 to be in a constitutively hyperphosphorylated state, irrespective of weak acid stress. Screening of non-essential protein kinase mutants of yeast failed to identify a kinase required for Pdr12 induction, or War1 hyperphosphorylation, in response to sorbate treatment. However, the mrk1∆ mutant was identified as having an elevated Pdr12 level in the absence of sorbate stress. Copyright © 2011 John Wiley & Sons, Ltd.

Copyright © 2011 John Wiley & Sons, Ltd.

PMID:
22113732
[PubMed - as supplied by publisher]
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18.
Exp Neurobiol. 2010 Dec;19(3):120-31. Epub 2010 Dec 31.

Drug development for Alzheimer's disease: recent progress.

Source

Institute for Brain Science and Technology (IBST)/Graduate Program in Neuroscience, Inje University, Busan 614-735, Korea.

Abstract

Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development.

PMID:
22110351
[PubMed]
PMCID: PMC3214787
Free PMC Article
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19.
J Biol Chem. 2011 Nov 18. [Epub ahead of print]

Evidence for the irreversible inhibition of glycogen synthase kinase-3β by tideglusib.

Source

Noscira S.A., Spain.

Abstract

Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer's disease and progressive supranuclear palsy. Sustained oral administration of the compound to a variety of animal models decreases tau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory and prevents neuronal loss. We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compounds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissociation rate although the drug retains its inhibitory activity with decreased potency and long residence time. In addition, tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of unspecific reactivity. Results obtained with [35S]-tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3β. The irreversibility of the inhibition and the very low protein turnover rate observed for the enzyme are particularly relevant from a pharmacological perspective and could have significant implications on its therapeutic potential.

PMID:
22102280
[PubMed - as supplied by publisher]
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20.
J Alzheimers Dis. 2011 Nov 18. [Epub ahead of print]

Endoplasmic Reticulum Stress Induces Tau Pathology and Forms a Vicious Cycle: Implication in Alzheimer's Disease Pathogenesis.

Source

Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Abstract

Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress andhyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration.

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