RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention

被引：713

作者：

Donnelly, Christopher J. ^{[1
,5
]}

Zhang, Ping-Wu ^{[1
,5
]}

Pham, Jacqueline T. ^{[3
]}

Heusler, Aaron R. ^{[4
]}

Mistry, Nipun A. ^{[1
,5
]}

Vidensky, Svetlana ^{[1
,5
]}

Daley, Elizabeth L. ^{[1
,5
]}

Poth, Erin M. ^{[2
]}

Hoover, Benjamin ^{[1
,5
]}

Fines, Daniel M. ^{[1
,5
]}

Maragakis, Nicholas ^{[1
]}

Tienari, Pentti J. ^{[6
,7
]}

Petrucelli, Leonard ^{[8
]}

Traynor, Bryan J. ^{[1
,9
]}

Wang, Jiou ^{[2
,4
]}

Rigo, Frank ^{[10
]}

Bennett, C. Frank ^{[10
]}

Blackshaw, Seth ^{[2
]}

Sattler, Rita ^{[1
,5
]}

Rothstein, Jeffrey D. ^{[1
,2
,3
,5
]}

机构：

[1] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Dept Cellular & Mol Med, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Brain Sci Inst, Baltimore, MD 21205 USA

[6] Univ Helsinki, Biomedicum, Res Programs Unit, FIN-00290 Helsinki, Finland

[7] Univ Helsinki, Cent Hosp, Dept Neurol, FIN-00290 Helsinki, Finland

[8] Mayo Clin, Dept Mol Neurosci, Jacksonville, FL 32224 USA

[9] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[10] ISIS Pharmaceut, Carlsbad, CA 92010 USA

来源：

NEURON | 2013年 / 80卷 / 02期

基金：

美国国家卫生研究院;

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; REPEAT EXPANSION; FRONTOTEMPORAL DEMENTIA; HEXANUCLEOTIDE REPEAT; GGGGCC REPEAT; GLUTAMATE TRANSPORTER; TIME-COURSE; IN-VIVO; PROTEINS; MECHANISMS;

D O I：

10.1016/j.neuron.2013.10.015

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCC(exp) RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.

引用

页码：415 / 428

页数：14

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