Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD

被引：204

作者：

Boeynaems, Steven ^{[1
,2
,3
]}

Bogaertl, Elke ^{[1
,2
,3
]}

Michiels, Emiel ^{[1
,2
,3
]}

Gijselinck, Ilse ^{[4
,5
]}

Sieben, Anne ^{[4
,5
,6
,7
]}

Jovicic, Ana ^{[8
]}

De Baets, Greet ^{[9
,10
]}

Scheveneels, Wendy ^{[1
,2
,3
]}

Steyaert, Jolien ^{[1
,2
,3
]}

Cuijt, Ivy ^{[4
,5
]}

Verstrepen, Kevin J. ^{[11
,12
]}

Callaerts, Patrick ^{[13
,14
]}

Rousseau, Frederic ^{[9
,10
]}

Schymkowitz, Joost ^{[9
,10
]}

Cruts, Marc ^{[4
,5
]}

Van Broeckhoven, Christine ^{[4
,5
]}

Van Damme, Philip ^{[1
,2
,3
,15
]}

Gitler, Aaron D. ^{[8
]}

Robberecht, Wim ^{[1
,2
,3
,15
]}

Van den Bosch, Ludo ^{[1
,2
,3
]}

机构：

[1] KU Leuven Univ Leuven, Dept Neurosci, Expt Neurol, B-3000 Leuven, Belgium

[2] Leuven Res Inst Neurosci & Dis LIND, B-3000 Leuven, Belgium

[3] VIB, Vesalius Res Ctr, Neurobiol Lab, B-3000 Leuven, Belgium

[4] VIB, Dept Mol Genet, B-2610 Antwerp, Belgium

[5] Univ Antwerp, Inst Born Bunge, B-2610 Antwerp, Belgium

[6] Univ Hosp Ghent, Dept Neurol, B-9000 Ghent, Belgium

[7] Univ Ghent, B-9000 Ghent, Belgium

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

[9] VIB, SWITCH Lab, B-3000 Leuven, Belgium

[10] Katholieke Univ Leuven, SWITCH Lab, Dept Cellular & Mol Med, B-3000 Leuven, Belgium

[11] VIB Lab Syst Biol, Gaston Geenslaan 1, B-3001 Leuven, Belgium

[12] KU Leuven Univ Leuven, Dept Microbial & Mol Syst, Lab Genet & Genom, Gaston Geenslaan 1, B-3001 Leuven, Belgium

[13] KU Leuven Univ Leuven, Dept Human Genet, Lab Behav & Dev Genet, B-3000 Leuven, Belgium

[14] VIB Ctr Biol Dis, B-3000 Leuven, Belgium

[15] Univ Hosp Leuven, Dept Neurol, B-3000 Leuven, Belgium

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

欧洲研究理事会;

关键词：

DIPEPTIDE-REPEAT PROTEINS; FRONTOTEMPORAL LOBAR DEGENERATION; NUCLEOCYTOPLASMIC TRANSPORT; HEXANUCLEOTIDE REPEAT; C9ORF72; MUTATION; GGGGCC REPEAT; RNA FOCI; ALS; EXPANSION; BINDING;

D O I：

10.1038/srep20877

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.

引用

页数：8

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