Association of Long ATXN2 CAG Repeat Sizes With Increased Risk of Amyotrophic Lateral Sclerosis
ABSTRACT To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS.
France and Quebec, Canada.
A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin.
We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases.
Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.
Full-textDOI: · Available from: Veronique V Belzil, Nov 11, 2014
- SourceAvailable from: Chen Yongping
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- "Single-nucleotide polymorphisms (SNPs) have an important function in the development of neurodegenerative disorders (Ramanan and Saykin, 2013). For example, polymorphisms in the promoter Rep1 of alpha-synuclein (SNCA), polyglutamine repeats in ATXN2, and Val343Ala in coenzyme Q2 4-hydroxybenzoate polyprenyltransferase increase the risk for PD (Mata et al., 2010), ALS (Daoud et al., 2011), and MSA (Collaboration, 2013), respectively. SNCA, which is encoded by the SNCA gene, is the major component of Lewy bodies and neurites, which are the pathologic hallmarks of PD (Mollenhauer et al., 2011). "
ABSTRACT: Previous studies found that polymorphisms rs2736990 and rs356220 in the alpha-synuclein (SNCA) gene increase the risk for Parkinson's disease (PD) in a Caucasian population. In consideration of the overlapping of clinical manifestations and pathologic characteristics among PD, amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA), the possible associations of these 2 polymorphisms and 3 neurodegenerative diseases were studied in the Chinese population. A total of 1011 PD, 778 sporadic ALS (SALS), 264 MSA patients, and 721 healthy controls (HCs) were studied. All subjects were genotyped for the 2 polymorphisms using polymerase chain reaction and direct sequencing. Significant differences in the genotype frequencies (p = 0.0188 and 0.0064, respectively) and minor allele frequencies (MAFs) (p = 0.0065 and 0.0095, respectively) of rs2736990 and rs356220 were observed between the PD patients and HCs. Moreover, significant differences were found between the early-onset PD patients (<50 years) and matched controls but not in the late-onset PD patients (≥50 years). However, no differences were observed between subgroups with regard to clinical features, such as sex, onset symptoms (tremor or rigidity), cognition (normal or abnormal), and anxiety and depression (presence or absence). No significant differences were found in the genotype frequencies and MAFs of these 2 single-nucleotide polymorphisms between SALS patients and HCs and between MSA patients and HCs. No significant differences were found between subgroups with regard to the clinical presentation of SALS and MSA. Our results show that rs2736990 and rs356220 in SNCA decreased the risk for PD in a Chinese population. These candidate polymorphisms were unlikely to be the causes of SALS and MSA in this population.Neurobiology of Aging 07/2014; 35(12). DOI:10.1016/j.neurobiolaging.2014.07.014 · 4.85 Impact Factor
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- "Further, an increase in ataxin-2 polyglutamine length is a risk factor for ALS demonstrating the clinical relevance of these findings [Elden et al., 2010; Daoud et al., 2011]. "
ABSTRACT: Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in Sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database(LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS.Human Mutation 06/2013; 34(6). DOI:10.1002/humu.22319 · 5.05 Impact Factor
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- "A trinucleotide repeat in ATXN2 exon 1, which codes for a polyglutamine (polyQ) domain, was found to expand from usually 22 U to 32 or more CAG units and thus cause this multisystem atrophy of the central nervous system through a gain-of-function mechanism (Auburger 2011). Intermediate and large expansions of 27–37 trinucleotide units, usually CAG repeats with CAA interruptions, were recently shown to contribute to the risk of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of the Parkinson plus syndrome Progressive Supranuclear Palsy (PSP) (Elden et al. 2010; Chen et al. 2011; Daoud et al. 2011; Gispert et al. 2011; Lee et al. 2011a, b; Ross et al. 2011; Soraru et al. 2011; Van Damme et al. 2011). In animal models, overexpression of ATXN2 potentiates toxicity from neurodegenerative disease proteins ATXN1, ATXN3, TDP-43, and MAPT, which are responsible for different variants of spinocerebellar ataxia, ALS, frontotemporal dementia, and PSP (Shulman and Feany 2003; Al-Ramahi et al. 2007; Lessing and Bonini 2008; Elden et al. 2010). "
ABSTRACT: Ataxin-2 (ATXN2) is implicated mainly in mRNA processing. Some ATXN2 associates with receptor tyrosine kinases (RTK), inhibiting their endocytic internalization through interaction of proline-rich domains (PRD) in ATXN2 with SH3 motifs in Src. Gain of function of ATXN2 leads to neuronal atrophy in the diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Conversely, ATXN2 knockout (KO) mice show hypertrophy and insulin resistance. To elucidate the influence of ATXN2 on trophic regulation, we surveyed interactions of ATXN2 with SH3 motifs from numerous proteins and observed a novel interaction with Grb2. Direct binding in glutathione S-transferase (GST) pull-down assays and coimmunoprecipitation of the endogenous proteins indicated a physiologically relevant association. In SCA2 patient fibroblasts, Grb2 more than Src protein levels were diminished, with an upregulation of both transcripts suggesting enhanced protein turnover. In KO mouse embryonal fibroblasts (MEF), the protein levels of Grb2 and Src were decreased. ATXN2 absence by itself was insufficient to significantly change Grb2-dependent signaling for endogenous Ras levels, Ras-GTP levels, and kinetics as well as MEK1 phosphorylation, suggesting that other factors compensate for proliferation control. In KO tissue with postmitotic neurons, a significant decrease of Src protein levels is prominent rather than Grb2. ATXN2 mutations modulate the levels of several components of the RTK endocytosis complex and may thus contribute to alter cell proliferation as well as translation and growth.Journal of Molecular Neuroscience 01/2013; 51(1). DOI:10.1007/s12031-012-9949-4 · 2.76 Impact Factor