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

Abstract

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.

• Authors: Andrew C Elden, Hyung-Jun Kim, Michael P Hart, Alice S Chen-Plotkin, Brian S Johnson, Xiaodong Fang, Maria Armakola, Felix Geser, Robert Greene, Min Min Lu, Arun Padmanabhan, Dana Clay-Falcone, Leo McCluskey, Lauren Elman, Denise Juhr, Peter J Gruber, Udo Rüb, Georg Auburger, John Q Trojanowski, Virginia M-Y Lee, Vivianna M Van Deerlin, Nancy M Bonini, Aaron D Gitler
• Journal: Nature (Nature) Vol. 466 Issue 7310 Pg. 1069-75 (Aug 26 2010) ISSN: 1476-4687 [Electronic] England
• PMID: 20740007 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ataxins
• DNA-Binding Proteins
• Nerve Tissue Proteins
• Peptides
• polyglutamine

Topics

• Adult
• Aged
• Aged, 80 and over
• Amyotrophic Lateral Sclerosis (genetics)
• Animals
• Ataxins
• Cell Line
• DNA-Binding Proteins (metabolism, toxicity)
• Drosophila (drug effects, genetics)
• Female
• Genetic Predisposition to Disease
• Humans
• Male
• Middle Aged
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (pathology)
• Peptides (chemistry, genetics)
• Repetitive Sequences, Amino Acid (genetics)
• Risk Factors
• Saccharomyces cerevisiae (drug effects, genetics, metabolism)
• Young Adult