Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

By Andrew C. Elden, Hyung-Jun Kim, Michael P. Hart, A. Chen-Plotkin, Brian S Johnson, X. Fang, Maria Armakola, F. Geser, Robert Greene, M. Lu and 13 more. Nature, 2010

1,315 citations recorded by the source corpus.

The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27–33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43–ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/a1d14f848d82de1484f85427042a9ef90e0f4691

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Citations in the corpus

The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease (2012, background): “This simple transforming principle helps establish the unfamiliar view of self-templating protein structures as genetic material (Fink, 2005).”
A census of human RNA-binding proteins (2014, background): “, 1995) ATXN2, ATXN2L spinocerebellar ataxia, susceptibility to lateonset Parkinson disease, susceptibility to amyotrophic lateral sclerosis (ALS) polyglutamine expansion leading to protein aggregation (Cancel et al., 1997; Elden et al., 2010; Gwinn-Hardy et al., 2000; Pulst et al., 1996)”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, neutral): “, 2011), ATXN2 (Ataxin-2) (Elden et al., 2010; Ross et al., 2011), OPTN (Optineurin) (Maruyama et al.”
Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue (2010, background): “A recent study by Gitler and colleagues demonstrated that ataxin-2 binds TDP-43 and expanded polyglutamine domains in ataxin-2 promote formation of TDP-43 inclusions [44].”
RNA Phase Transitions in Repeat Expansion Disorders (2017, neutral): “Our results also may explain why placement of distinct repeat expansions in seemingly unrelated genes can result in similar clinical syndromes 39,40 .”
Stress granules as crucibles of ALS pathogenesis (2013, background): “Ataxin 2, SGs, and disease: integrating environmental stress and disease? Ataxin 2 is another SG-associated RNA-binding protein that contributes to neurodegenerative disease (Elden et al., 2010; Orr and Zoghbi, 2007).”
Amyotrophic lateral sclerosis: a clinical review (2020, background): “An at risk genotype is UNC13A [32], and intermediate repeat expansions in ATXN2 increase the risk of getting ALS [33,34].”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, neutral): “, 2004), and ataxin-2 (Elden et al., 2010), disruption in RNA homeostasis seems highly likely to play a central role in ALS pathogenesis.”
Compositional Control of Phase-Separated Cellular Bodies (2016, neutral): “Indeed, in models of ALS, toxicities due to TDP-43 aggregation can be alleviated by removal of the Ataxin-2 scaffold (Elden et al., 2010).”