The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS

被引：1017

作者：

Mori, Kohji ^{[1
]}

Weng, Shih-Ming ^{[2
]}

Arzberger, Thomas ^{[3
]}

May, Stephanie ^{[2
]}

Rentzsch, Kristin ^{[2
]}

Kremmer, Elisabeth ^{[4
]}

Schmid, Bettina ^{[2
,5
]}

Kretzschmar, Hans A. ^{[3
]}

Cruts, Marc ^{[6
,7
]}

Van Broeckhoven, Christine ^{[6
,7
]}

Haass, Christian ^{[1
,2
,5
]}

Edbauer, Dieter ^{[1
,2
,5
]}

机构：

[1] Univ Munich, Adolf Butenandt Inst, D-80336 Munich, Germany

[2] German Ctr Neurodegenerat Dis DZNE, D-80336 Munich, Germany

[3] Univ Munich, Ctr Neuropathol & Prion Res, D-81377 Munich, Germany

[4] Helmholtz Zentrum Munchen, Inst Mol Immunol, D-81377 Munich, Germany

[5] Univ Munich, Munich Cluster Syst Neurol SyNergy, D-80336 Munich, Germany

[6] Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, B-2610 Antwerp, Belgium

[7] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2610 Antwerp, Belgium

来源：

SCIENCE | 2013年 / 339卷 / 6125期

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL DEMENTIA; HEXANUCLEOTIDE REPEAT; EXPANSION; IDENTIFICATION; INITIATION; FTD; ALS;

D O I：

10.1126/science.1232927

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：

Expansion of a GGGGCC hexanucleotide repeat upstream of the C9orf72 coding region is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS), but the pathomechanisms involved are unknown. As in other FTLD/ALS variants, characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown. Here, we found that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in three reading frames. These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion.

引用

页码：1335 / 1338

页数：5

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