肌萎縮性側(cè)索硬化癥” (ALS)也被稱為“Lou Gehrig’s癥”,，它是一種常見的成人型神經(jīng)退行性疾病,，是不可治愈的。ALS大部分是零星發(fā)生的,，但約有10%的病例也有一個家族成分,，最常見的是SOD1（超氧化物岐化酶）基因。然而SOD1突變只占全部病例的約2%,，所以尋找其他ALS風(fēng)險因子的工作還在繼續(xù),。蛋白TDP-43被認(rèn)為在ALS發(fā)病中扮演一個角色,，但尚未確定,；Elden等人發(fā)現(xiàn)，ataxin-2（一種多谷氨酰胺(polyQ)蛋白，在2-型脊髓小腦萎縮癥中發(fā)生突變）在動物和細(xì)胞模型中是TDP-43毒性的一個強(qiáng)效修飾因子,。對915個人所做的DNA分析顯示,，ATXN2是一個相對比較常見的ALS病易感基因，占ALS病例的近4.7%,。這些發(fā)現(xiàn)表明,，TDP-43/ataxin-2互動是治療干預(yù)的一個可能目標(biāo)。（生物谷Bioon.com）
生物谷推薦原文出處：
Nature doi:10.1038/nature09320
Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS
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
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.
