Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.
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.
Elden
Andrew C
AC
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Kim
Hyung-Jun
HJ
Hart
Michael P
MP
Chen-Plotkin
Alice S
AS
Johnson
Brian S
BS
Fang
Xiaodong
X
Armakola
Maria
M
Geser
Felix
F
Greene
Robert
R
Lu
Min Min
MM
Padmanabhan
Arun
A
Clay-Falcone
Dana
D
McCluskey
Leo
L
Elman
Lauren
L
Juhr
Denise
D
Gruber
Peter J
PJ
Rüb
Udo
U
Auburger
Georg
G
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
Van Deerlin
Vivianna M
VM
Bonini
Nancy M
NM
Gitler
Aaron D
AD
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
D000067528:Ataxins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine