Repeated repeat problems: Combinatorial effect of C9orf72-derived dipeptide repeat proteins

被引：11

作者：

Darling, April L. ^{[1
]}

Breydo, Leonid ^{[1
]}

Rivas, Emma G. ^{[1
]}

Gebru, Niad T. ^{[1
]}

Zheng, Dali ^{[1
]}

Baker, Jeremy D. ^{[1
]}

Blair, Laura J. ^{[1
]}

Dickey, Chad A. ^{[1
]}

Koren, John, III ^{[1
]}

Uversky, Vladimir N. ^{[1
,2
]}

机构：

[1] Univ S Florida, Byrd Alzheimers Inst, Coll Med, Dept Mol Med, Tampa, FL 33612 USA

[2] Russian Acad Sci, Inst Biol Instrumentat, Pushchino 142290, Moscow Region, Russia

来源：

INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES | 2019年 / 127卷

关键词：

C9orf72; Dipeptide repeat protein; ALS; FTD; Poly(GA); Poly(PR); Intrinsically disordered proteins; NUCLEAR-RNA FOCI; HEXANUCLEOTIDE REPEAT; PHASE-TRANSITION; GGGGCC REPEAT; IN-VITRO; C9ORF72; EXPANSION; COMPLEXITY; TOXICITY; TRANSLATION;

D O I：

10.1016/j.ijbiomac.2019.01.035

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A microsatellite expansion mutation in C9orf72 is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The expansion mutation leads to C9orf72 loss of function, RNA foci formation, and generation of five species of non-AUG RAN translated dipeptide repeat proteins (DPRs), such as poly(GA), poly(GP), poly(GR), poly(PA), and poly(PR). Although one cell can contain more than type of DPRs, information about interplay between different DPR species is limited. Here we show that the combined expression of distinct C9orf72-derived dipeptide repeat species produces cellular outcomes and structural differences that are unique compared to the expression of a single DPR species, suggesting the complex biological interactions that occur when multiple DPR variants are simultaneously expressed. Our data highlights the need for further analysis of how combined expression of different DPRs affects the disease state. (C) 2019 Published by Elsevier B.V.

引用

页码：136 / 145

页数：10

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