Publikationsdatum:
2010-08-27
Beschreibung:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965417/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965417/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elden, Andrew C -- Kim, Hyung-Jun -- Hart, Michael P -- Chen-Plotkin, Alice S -- Johnson, Brian S -- Fang, Xiaodong -- Armakola, Maria -- Geser, Felix -- Greene, Robert -- Lu, Min Min -- Padmanabhan, Arun -- Clay-Falcone, Dana -- McCluskey, Leo -- Elman, Lauren -- Juhr, Denise -- Gruber, Peter J -- Rub, Udo -- Auburger, Georg -- Trojanowski, John Q -- Lee, Virginia M-Y -- Van Deerlin, Vivianna M -- Bonini, Nancy M -- Gitler, Aaron D -- 1DP2OD004417-01/OD/NIH HHS/ -- 1R01NS065317-01/NS/NINDS NIH HHS/ -- AG-10124/AG/NIA NIH HHS/ -- AG-17586/AG/NIA NIH HHS/ -- DP2 OD004417/OD/NIH HHS/ -- DP2 OD004417-01/OD/NIH HHS/ -- K08 AG-033101-01/AG/NIA NIH HHS/ -- P01 AG-09215/AG/NIA NIH HHS/ -- R01 NS065317/NS/NINDS NIH HHS/ -- R01 NS065317-01/NS/NINDS NIH HHS/ -- R01 NS065317-02/NS/NINDS NIH HHS/ -- R01 NS065317-03/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Aug 26;466(7310):1069-75. doi: 10.1038/nature09320.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20740007" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
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
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
Permalink
