title: 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.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Elden
authors.forename: Hyung-Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hart
authors.forename: Alice S
authors.initials: AS
authors.lastname: Chen-Plotkin
authors.forename: Brian S
authors.initials: BS
authors.lastname: Johnson
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Fang
authors.forename: Maria
authors.initials: M
authors.lastname: Armakola
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: Robert
authors.initials: R
authors.lastname: Greene
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.forename: Arun
authors.initials: A
authors.lastname: Padmanabhan
authors.forename: Dana
authors.initials: D
authors.lastname: Clay-Falcone
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.forename: Denise
authors.initials: D
authors.lastname: Juhr
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D000067528:Ataxins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000633:toxicity; D004330:Drosophila / Q000187:drug effects / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000235:genetics*; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics*; D012307:Risk Factors; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000067528:Ataxins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine