Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS

被引：469

作者：

Jovicic, Ana ^{[1
]}

Mertens, Jerome ^{[2
]}

Boeynaems, Steven ^{[3
,4
,5
]}

Bogaert, Elke ^{[3
,4
,5
]}

Chai, Noori ^{[1
,6
]}

Yamada, Shizuka B. ^{[1
,7
]}

Paul, Joseph W., III ^{[1
]}

Sun, Shuying ^{[8
,9
]}

Herdy, Joseph R. ^{[2
]}

Bieri, Gregor ^{[1
,6
]}

Kramer, Nicholas J. ^{[1
,6
]}

Gage, Fred H. ^{[2
]}

Van den Bosch, Ludo ^{[3
,4
,5
]}

Robberecht, Wim ^{[3
,4
,5
,10
]}

Gitler, Aaron D. ^{[1
]}

机构：

[1] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[2] Salk Inst Biol Studies, Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA

[3] Univ Leuven, KU Leuven, Dept Neurosci, Expt Neurol, Leuven, Belgium

[4] Leuven Res Inst Neurosci & Dis LIND, Leuven, Belgium

[5] VIB, Vesalius Res Ctr, Neurobiol Lab, Leuven, Belgium

[6] Stanford Univ, Sch Med, Neurosci Grad Program, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Biol, Stanford, CA 94305 USA

[8] Univ Calif San Diego, Ludwig Inst Canc Res, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[9] Univ Calif San Diego, Ludwig Inst Canc Res, Dept Neurosci, La Jolla, CA 92093 USA

[10] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium

来源：

NATURE NEUROSCIENCE | 2015年 / 18卷 / 09期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

HEXANUCLEOTIDE REPEAT; RNA FOCI; PROTEINS; ALS; EXPANSIONS; PATHOLOGY;

D O I：

10.1038/nn.4085

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.

引用

页码：1226 / +

页数：6

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