1.
ENU Mutagenesis Screen to Establish Motor Phenotypes in Wild-Type Mice and Modifiers of a Pre-Existing Motor Phenotype in Tau Mutant Mice.
Source
Alzheimer's and Parkinson's Disease Laboratory, Brain & Mind Research Institute, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia.
Abstract
Modifier screening is a powerful genetic tool. While not widely used in the vertebrate system, we applied these tools to transgenic mouse strains that recapitulate key aspects of Alzheimer's disease (AD), such as tau-expressing mice. These are characterized by a robust pathology including both motor and memory impairment. The phenotype can be modulated by ENU mutagenesis, which results in novel mutant mouse strains and allows identifying the underlyinggene/mutation. Here we discuss this strategy in detail. We firstly obtained pedigrees that modify the tau-related motor phenotype, with mapping ongoing. We further obtained transgene-independent motor pedigrees: (i) hyperactive, circling ENU 37 mice with a causal mutation in the Tbx1 gene-the complete knock-out of Tbx1 models DiGeorge Syndrome; (ii) ENU12/301 mice that show sudden jerky movements and tremor constantly; they have a causal mutation in the Kcnq1gene, modelling aspects of the Romano-Ward and Jervell and Lange-Nielsen syndromes; and (iii) ENU16/069 mice with tremor and hypermetric gait that have a causal mutation in the Mpz (Myelin Protein Zero) gene, modelling Charcot-Marie-Tooth disease type 1 (CMT1B). Together, we provide evidence for a real potential of an ENU mutagenesis to dissect motor functions in wild-type and tau mutant mice.
- PMID:
- 22219655
- [PubMed - in process]
Constructing Logical Models of Gene Regulatory Networks by Integrating Transcription Factor-DNA Interactions with Expression Data: An Entropy-Based Approach.
Source
Blavatnik School of Computer Science, Tel Aviv University , Tel Aviv, Israel .
Abstract
Abstract Models of gene regulatory networks (GRNs) attempt to explain the complex processes that determine cells' behavior, such as differentiation, metabolism, and the cell cycle. The advent of high-throughput data generation technologies has allowed researchers to fit theoretical models to experimental data on gene-expression profiles. GRNs are often represented using logical models. These models require that real-valued measurements be converted to discrete levels, such as on/off, but the discretization often introduces inconsistencies into the data. Dimitrova et al. posed the problem of efficiently finding a parsimonious resolution of the introduced inconsistencies. We show that reconstruction of a logical GRN that minimizes the errors is NP-complete, so that an efficient exact algorithm for the problem is not likely to exist. We present a probabilistic formulation of the problem that circumvents discretization of expression data. We phrase the problem of error reduction as a minimum entropy problem, develop a heuristic algorithm for it, and evaluate its performance on mouse embryonic stem cell data. The constructed model displays high consistency with prior biological knowledge. Despite the oversimplification of a discrete model, we show that it is superior to raw experimental measurements and demonstrates a highly significant level of identical regulatory logic among co-regulated genes. A software implementing the method is freely available at: http://acgt.cs.tau.ac.il/modent.
- PMID:
- 22216865
- [PubMed - in process]
Direct effect of acaricides on pathogen loads and gene expression levels of honey bee Apis mellifera.
Source
USDA-ARS Bee Research Lab, BARC-East Bldg. 476, Beltsville, MD 20705, USA; Department of Biology, Univ. North Carolina at Greensboro, 312 Eberhart Bldg. Greensboro, NC 27403, USA.
Abstract
The effect of using acaricides to control varroa mites has long been a concern to the beekeeping industry due to unintended negative impacts on honey bee health. Irregular ontogenesis, suppression of immune defenses, and impairment of normal behavior have been linked to pesticide use. External stressors, including parasites and the pathogens they vector, can confound studies on the effects of pesticides on the metabolism of honey bees. This is the case of Varroa destructor, a mite that negatively affects honey bee health on many levels, from direct parasitism, which diminishes honey bee productivity, to vectoring and/or activating other pathogens, including many viruses. Here we present a gene expression profile comprising genes acting on diverse metabolic levels (detoxification, immunity, and development) in a honey bee population that lacks the influence of varroa mites. We present data for hives treated with five different acaricides; Apiguard (thymol), Apistan (tau-fluvalinate), Checkmite (coumaphos), Miteaway (formic acid) and ApiVar (amitraz). The results indicate that thymol, coumaphos and formic acid are able to alter some metabolic responses. These include detoxification gene expression pathways, components of the immune system responsible for cellular response and the c-Jun amino-terminal kinase (JNK) pathway, and developmental genes. These could potentially interfere with the health of individual honey bees and entire colonies.
Copyright © 2011. Published by Elsevier Ltd.
Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions.
Source
Department of Neuroscience, Uppsala University, Box 593, Husargatan 3, Uppsala, Sweden.
Abstract
Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.
Regulation of Physiologic Actions of LRRK2: Focus on Autophagy.
Source
Department of Pharmacology, Boston University School of Medicine, Boston, Mass., USA.
Abstract
Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. Objectives: To investigate mechanisms by which LRRK2 might cause PD. Methods: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. Results: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. Conclusion: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.
Copyright © 2011 S. Karger AG, Basel.
Follicular Growth-Stimulated Cows Provide Favorable Oocytes for Producing Cloned Embryos.
Source
1 National Livestock Breeding Center , Nishigo, Fukushima, Japan .
Abstract
Abstract We examined the influence of recipient oocytes on in vitro development, oxygen consumption, and geneexpression in the resulting cloned bovine embryos. Oocytes derived from slaughterhouse ovaries and ovum pickup (OPU)-derived oocytes were used as recipient cytoplasts for the production of cloned embryos. A series of OPU sessions was conducted on Holstein cows without follicular growth treatment (FGT). In the same cows, we then performed dominant follicle ablation and subsequently administered follicle-stimulating hormone and prostaglandin F(2α) with controlled internal drug release device before a second series of OPU. Cumulus cells collected from single Holstein cows were used as donor cells. After measurement of oxygen consumption at the blastocyst stage with modified scanning electrochemical microscopy, analysis of 10 genes (CDX2, IFN-tau, PLAC8, OCT4, SOX2, NANOG, ATP5A1, GLUT1, AKR1B1, and IGF2R) was performed with real-time RT-PCR. Rates of fusion, cleavage, and blastocyst formation were not different among the treatment groups. Levels of oxygen consumption in cloned blastocysts derived from slaughterhouse ovaries or OPU without FGT were significantly lower than in blastocysts derived from artificial insemination (AI). However, oxygen consumption was increased in cloned blastocysts derived from OPU with FGT, depending on the individual oocyte donor. Furthermore, gene expression of IFN-tau and OCT4 in cloned blastocysts derived from OPU with FGT was similar to that in AI-derived blastocysts, whereas expression of those genes in cloned blastocysts derived from slaughterhouse ovaries or OPU without FGT was significantly different from that in AI-derived blastocysts. Thus, recipient oocytes collected by OPU in combination with manipulation of follicular growth in donor cows are suitable for producing cloned embryos.
- PMID:
- 22204594
- [PubMed - as supplied by publisher]
Tau's role in the developing brain: implications for intellectual disability.
Source
Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel.
Abstract
Microdeletions encompassing the MAPT (Tau) locus resulting in intellectual disability raised the hypothesis that Taumay regulate early functions in the developing brain. Our results indicate that neuronal migration was inhibited in mouse brains following Tau reduction. In addition, the leading edge of radially migrating neurons was aberrant in spite of normal morphology of radial glia. Furthermore, intracellular mitochondrial transport and morphology were affected. In early postnatal brains, a portion of Tau knocked down neurons reached the cortical plate. Nevertheless, they exhibited far less developed dendrites and a striking reduction in connectivity evident by the size of boutons. Our novel results strongly implicate MAPT as a dosage-sensitive gene in this locus involved in intellectual disability. Furthermore, our results are likely to impact our understanding of other diseases involving Tau.
Olfaction in Parkinson's disease and related disorders.
Abstract
Olfactory dysfunction is an early 'pre-clinical' sign of Parkinson's disease (PD). The present review is a comprehensive and up-to-date assessment of such dysfunction in PD and related disorders. The olfactory bulb is implicated in the dysfunction, since only those syndromes with olfactory bulb pathology exhibit significant smell loss. The role of dopamine in the production of olfactory system pathology is enigmatic, as overexpression of dopaminergic cells within the bulb's glomerular layer is a common feature of PD and most animal models of PD. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with the most smell loss. When compromised, these systems, which regulate microglial activity, can influence the induction of localized brain inflammation, oxidative damage, and cytosolic disruption of cellular processes. In monogenetic forms of PD, olfactory dysfunction is rarely observed in asymptomatic gene carriers, but is present in many of those that exhibit the motor phenotype. This suggests that such gene-related influences on olfaction, when present, take time to develop and depend upon additional factors, such as those from aging, other genes, formation of α-synuclean- and tau-related pathology, or lowered thresholds to oxidative stress from toxic insults. The limited data available suggest that the physiological determinants of the early changes in PD-related olfactory function are likely multifactorial and may include the same determinants as those responsible for a number of other non-motor symptoms of PD, such as dysautonomia and sleep disturbances.
Copyright © 2011 Elsevier Inc. All rights reserved.
Mouse models for LRRK2 Parkinson's disease.
Source
Department of Neurology and Friedman Brain Institute, Mt. Sinai School of Medicine, New York University, New York, NY 10029, USA.
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2), the causative gene for PARK8 type PD with autosomal dominant inheritance, are the most prevalent genetic causes of both familial and sporadic PD. Animal models are critical tools in the attempt to understand the mechanisms of LRRK2-mediated pathogenesis. We have generated human Bacterial Artificial Chromosome (BAC) mediated transgenic mouse models expressing mutant LRRK2 that robustly recapitulate the behavioral, neurochemical and pathological features of PD. These mice develop an age-dependent decrease in motor activity that is progressive and responds to treatment with levodopa. Pathologically, the most salient phenotype is early axonopathy of nigrostriatal dopaminergic neurons, accompanied by hyperphosphorylated tau. The mice also exhibit a consistent dopamine transmission deficit in both acute brain slices and live freely moving animals. Here we will discuss LRRK2 mouse models from several laboratories, their commonalities and differences, and offer scientific insights drawn from these studies.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Saitohin polymorphism and executive dysfunction in schizophrenia.
Source
Department of Clinical Neurosciences, San Raffaele Scientific Institute, Milan, Italy, bosia.marta@hsr.it.
Abstract
Saitohin (STH) is an intronless gene nested within the human tau gene, which contains a single nucleotide polymorphism (A/G), suggested to be involved in the physiopathology and clinical course of several neurodegenerative and neuropsychiatric diseases. Recently, an association between this polymorphism and frontal hypoperfusion and clinical prognosis in frontotemporal dementia was reported. The present study sought to evaluate the possible role of the STH polymorphism as a concurring factor of cognitive decline in schizophrenia, a disease sharing both early psychotic manifestations, a core deficit of executive functions and hypofrontality with frontotemporal lobe dementia. 220 clinically stabilized patients with schizophrenia were assessed with the Wisconsin Card Sorting Test (WCST) for evaluation of executive functions and compared for STH allele frequency with 48 patients affected by frontotemporal dementia and 47 healthy subjects. There was no significant difference in allelic distribution between the healthy controls and all other groups, while we observed a significantly greater frequency of G allele among both patients with frontotemporal dementia (p = 0.037) and schizophrenia patients with poor performances of WCST (p = 0.044), compared to schizophrenia patients with best WCST performances. Among the patients with schizophrenia, stratified for age and gender, the STH polymorphism resulted in a significant predictor of WCST performance (p = 0.007). These results suggest a possible contribution of STH gene products on the heterogeneity of core frontal executive functions deterioration, probably through complex interactions with mechanism involved in neurodevelopment and neurodegeneration.
Efficient algorithms for reconstructing gene content by co-evolution.
Source
Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel. tamirtul@post.tau.ac.il.
Abstract
BACKGROUND:
In a previous study we demonstrated that co-evolutionary information can be utilized for improving the accuracy of ancestral gene content reconstruction. To this end, we defined a new computational problem, the Ancestral Co-Evolutionary (ACE) problem, and developed algorithms for solving it.
RESULTS:
In the current paper we generalize our previous study in various ways. First, we describe new efficient computational approaches for solving the ACE problem. The new approaches are based on reductions to classical methods such as linear programming relaxation, quadratic programming, and min-cut. Second, we report new computational hardness results related to the ACE, including practical cases where it can be solved in polynomial time.Third, we generalize the ACE problem and demonstrate how our approach can be used for inferring parts of the genomes of non-ancestral organisms. To this end, we describe a heuristic for finding the portion of the genome ('dominant set') that can be used to reconstruct the rest of the genome with the lowest error rate. This heuristic utilizes both evolutionary information and co-evolutionary information.We implemented these algorithms on a large input of the ACE problem (95 unicellular organisms, 4,873 protein families, and 10, 576 of co-evolutionary relations), demonstrating that some of these algorithms can outperform the algorithm used in our previous study. In addition, we show that based on our approach a 'dominant set' cab be used reconstruct a major fraction of a genome (up to 79%) with relatively low error-rate (e.g. 0.11). We find that the 'dominant set' tends to include metabolic and regulatory genes, with high evolutionary rate, and low protein abundance and number of protein-protein interactions.
CONCLUSIONS:
The ACE problem can be efficiently extended for inferring the genomes of organisms that exist today. In addition, it may be solved in polynomial time in many practical cases. Metabolic and regulatory genes were found to be the most important groups of genes necessary for reconstructing gene content of an organism based on other related genomes.
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 genedosage 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.
Differential Conditions for Early Afterdepolarizations and Triggered Activity in Cardiomyocytes Derived from Transgenic LQT1 and LQT2 rabbits.
Source
Rhode Island Hospital and Brown University;
Abstract
ABSTRACTEarly afterdepolarization (EAD), or abnormal depolarization during the plateau phase of action potentials, is a hallmark of long-QT syndrome (LQTS). More than 13 genes have been identified as responsible for LQTS, and elevated risks for EADs may depend on genotypes such as exercise in LQT1 vs. sudden arousal in LQT2 patients. We investigated mechanisms underlying different high-risk conditions that trigger EADs using transgenic rabbit models of LQT1 and LQT2, which lack IKs and IKr, respectively. Single-cell patch clamp studies show that prolongation of APDs can be further enhanced by lowering [K]o from 5.4 to 3.6 mM. However, only LQT2 myocytes developed spontaneous EADs following perfusion with lower [K]o, while there was no EAD formation in littermate control (LMC) or LQT1 myocytes, although APDs were also prolonged in LMC myocytes and LQT1 myocytes. Isoproterenol (ISO) prolonged APDs and triggered EADs in LQT1 myocytes in the presence of lower [K]o. In contrast, continuous ISO perfusion diminished APD prolongation and reduced the incidence of EADs in LQT2 myocytes. These different ISO effects on LQT1 and LQT2 were verified in optical mapping of the whole heart, suggesting that ISO-induced EADs are genotype specific. Further voltage clamp studies revealed that ISO increases ICa faster than IKs (τ =9.2 s for ICa and 43.6 s for IKs), and computer simulation demonstrated a high-risk window of EADs in LQT2 during ISO perfusion due to mismatch in the time courses of ICa and IKs, which may explain why sympathetic surge rather than high sympathetic tone can be an effective trigger of EADs in LQT2 perfused hearts. In summary, EAD formation is genotype specific, such that EADs can be elicited in LQT2 myocytes simply by lowering [K]o, while LQT1 myocytes require sympathetic stimulation. Slower activation of IKs than of ICa by ISO may explain why different sympathetic modes, i.e., sympathetic surge vs. high sympathetic tone, are associated with polymorphic ventricular tachycardia (pVT) in LQTS patients.
Frontotemporal lobar degeneration related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus.
Source
Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA.
Abstract
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that involves cognitive decline and dementia. To model the hippocampal neurodegeneration and memory-related behavioral impairment that occurs in FTLD and othertau and TDP-43 proteinopathy diseases, we used an adeno-associated virus serotype 9 (AAV9) vector to induce bilateral expression of either microtubule-associated protein tau or transactive response DNA binding protein 43kDa (TDP-43) in adult rat dorsal hippocampus. Human wild-type forms of tau or TDP-43 were expressed. The vectors/doses were designed for moderate expression levels within neurons. Rats were evaluated for acquisition and retention in the Morris water task over 12weeks after gene transfer. Neither vector altered acquisition performance compared to controls. In measurements of retention, there was impairment in the TDP-43 group. Histological examination revealed specific loss of dentate gyrus granule cells and concomitant gliosis proximal to the injection site in the TDP-43 group, with shrinkage of the dorsal hippocampus. Despite specific tau pathology, the tau gene transfer surprisingly did not cause obvious neuronal loss or behavioral impairment. The data demonstrate that TDP-43 produced mild behavioral impairment and hippocampal neurodegeneration in rats, whereas tau did not. The models could be of value for studying mechanisms of FTLD and other diseases with tau and TDP-43 pathology in the hippocampus including Alzheimer's disease, with relevance to early stage mild impairment.
Copyright © 2011. Published by Elsevier Inc.
Roles of the Tau gene short tandem repeats in late-onset Alzheimer's Disease.
Source
Department of Neurology, Affiliated Hospital of Guiyang Medical College , Guiyang, Guizhou 550001 , China.
Abstract
Abstract This study assessed the roles of Tau gene short tandem repeats (STRs) nested within intron 1 (rs5820604 and rs10675722) and Apolipoprotein E (ApoE) gene polymorphisms, in 70 late-onset Alzheimer's disease (AD), 70 vascular dementia (VD) and 70 normal controls (NC) in Guizhou Han population. Our data suggest that the Tau gene STR loci rs5820604 (CA)(19) allele may increase the risk of AD, whereas the (CA)(16) allele may be protective. The Tau geneSTR loci rs10675722 (TA)(17) allele may increase the risk for AD and VD. In addition, a synergistic effect of polymorphisms in ApoE ε4 and Tau gene STR loci rs5820604 (CA)(19) allele was found in the pathogenesis of AD (P = 0.025, OR = 3.178, 95%CI = 1.156-8.741).
Loss of dopaminoreceptive neuron causes L-dopa resistant parkinsonism in tauopathy.
Source
Department of Pathology and Cell Biology, University of the Ryukyus Graduate School of Medicine, Okinawa, Japan; Department of Regenerative Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan.
Abstract
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a family of inherited dementias caused by tauopathy. A mutation in exon 10 of the tau gene, N279K, causes a particular kindred of FTDP-17, which is predominant for parkinsonism. The disease initially presents as L-dopa resistant parkinsonism which then rapidly progresses. The final pathological features reveal disappearing dopamine (DA) neurons, but the causes remain poorly understood. We previously established a transgenic mouse with human N279K mutant tau as a model for FTDP-17, which showed cognitive dysfunctions caused by the mutant. Here we analyze L-dopa resistant parkinsonism by several behavioral tests, and focus on the distributions and accumulations of the mutant tau in the DA system by immunohistochemistry and Western blot. Interestingly, dopaminoreceptive (DAr) neurons in the striatum showed neurofibrils degeneration and apoptosis through caspase-3 activation by mutant tau accumulation. The DAr neuron loss in the caudoputamen, the target of the nigrostriatal system occurred before DA neuron loss in young symptomatic mice. Residual DA neurons in the mouse functioned in DA transportation, whereas dysregulation of intracellular DA compartmentalization implied an excess level of DA caused by DAr neuron loss. In the final stages, both DAr and DA neurons decreased equally, unlike Parkinson's disease. Therefore, DAr neurons were fundamentally vulnerable to the mutation indicating a critical role for the L-dopa resistant parkinsonism in tauopathy.
Copyright © 2011 Elsevier Inc. All rights reserved.
BETA-AMYLOID CARRYING THE DUTCH MUTATION HAS DIVERSE EFFECTS ON CALPAIN-MEDIATED TOXICITY IN HIPPOCAMPAL NEURONS.
Source
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Abstract
Hereditary cerebral hemorrhage with amyloidosis-Dutch type is a disorder associated with a missense mutation (E693Q) in the beta-amyloid (Aβ)-coding region of the amyloid precursor protein. This familial disease is characterized by cognitive deficits secondary to intracerebral hemorrhage and, in some cases, progressive Alzheimer disease (AD)-like dementia. Although this mutation was the first ever reported in the human APP gene, little is known about the molecular mechanisms underlying the direct toxic effects of this mutated Aβ on central neurons. In the present study, we assessed the role of calpain-mediated toxicity in such effects using an AD primary culture model system. Our results showed that Dutch mutant Aβ (E22Q) induced calpain-mediated cleavage of dynamin 1 and a significant decrease in synaptic contacts in mature hippocampal cultures. These synaptic deficits were similar to those induced by wild type Aβ. In contrast, calpain-mediated tau cleavage leading to the generation of a 17 kDa neurotoxic fragment, as well as neuronal death, were significantly reduced in E22Q Aβ-treated neurons when compared to WT Aβ-treated ones. This complex regulation of the calpain-mediated toxicity pathway by E22Q Aβ could have some bearings in the pathobiology of this familial AD form.
The D1152H cystic fibrosis mutation in prenatal carrier screening, patients and prenatal diagnosis.
Source
The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel; epras@post.tau.ac.il.
Abstract
OBJECTIVE:
To assess the frequency of the D1152H mutation in the CFTR gene in normal individuals, in cystic fibrosis (CF) patients and in the setting of prenatal diagnosis.
SETTING:
A database analysis of sequential screening results seen at the Sheba Medical Center, Israel, between 2001 and 2010.
METHODS:
We retrospectively analyzed the frequency of D1152H in a large cohort of healthy individuals who were screened as part of a routine prenatal care programme, in individuals referred due to CF-related symptoms and in the setting of prenatal diagnosis.
RESULTS:
We found one asymptomatic homozygous female and 195 D1152H carriers among 49,940 healthy individuals screened, establishing a carrier rate of 1:255 for this mutation. We detected D1152H in nine of 103 individuals referred due to CF-related symptoms. Four suffered from respiratory symptoms and five from congenital bilateral absence of the vas deferens (CBAVD). During this period D1152H was detected in three pregnancies, two of which were aborted.
CONCLUSION:
The increased frequency of D1152H in individuals referred due to CF-related symptoms compared with healthy individuals included in the CF carrier screening programme (P < 0.001) clearly indicates that it is a disease-causing mutation.
First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation.
Source
Department of Clinical Science, Section of Geriatric Psychiatry, Lund University, Sweden; Department of Neurology, Lund, Skåne University Hospital, Sweden; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Abstract
The c.4309A>C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tauwas mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease.
Source
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
Abstract
Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer's disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75(NTR) to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75(NTR) and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75(NTR)-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75(NTR)-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75(NTR)-labeled NB neurons compared with Rac1b-negative/p75(NTR)-positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD.
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