RAN Translation in Huntington Disease

被引：259

作者：

Banez-Coronel, Monica ^{[1
,2
]}

Ayhan, Fatma ^{[1
,2
]}

Tarabochia, Alex D. ^{[1
,2
]}

Zu, Tao ^{[1
,2
]}

Perez, Barbara A. ^{[1
,2
]}

Tusi, Solaleh Khoramian ^{[1
,2
,6
]}

Pletnikova, Olga ^{[7
]}

Borchelt, David R. ^{[1
,4
]}

Ross, Christopher A. ^{[8
,9
,10
,11
,12
,13
,14
]}

Margolis, Russell L. ^{[8
,9
,10
,12
,14
]}

Yachnis, Anthony T. ^{[5
]}

Troncoso, Juan C. ^{[7
,10
]}

Ranum, Laura P. W. ^{[1
,2
,3
,6
]}

机构：

[1] Univ Florida, Ctr NeuroGenet, Coll Med, Gainesville, FL 32610 USA

[2] Univ Florida, Dept Mol Genet & Microbiol, Coll Med, Gainesville, FL 32610 USA

[3] Univ Florida, Dept Neurol, Coll Med, Gainesville, FL 32610 USA

[4] Univ Florida, Dept Neurosci, Coll Med, Gainesville, FL 32610 USA

[5] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA

[6] Univ Florida, Genet Inst, Gainesville, FL 32610 USA

[7] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Div Neurobiol, Baltimore, MD 21205 USA

[9] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA

[10] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[11] Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21205 USA

[12] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[13] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD 21205 USA

[14] Johns Hopkins Univ, Sch Med, Baltimore Huntingtons Dis Ctr, Baltimore, MD 21205 USA

来源：

NEURON | 2015年 / 88卷 / 04期

关键词：

MICROGLIAL ACTIVATION; TRINUCLEOTIDE REPEAT; MUTANT HUNTINGTIN; MOUSE MODELS; IN-VIVO; MICE; DEGENERATION; PATHOGENESIS; TRANSCRIPTS; POLYALANINE;

D O I：

10.1016/j.neuron.2015.10.038

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Huntington disease (HD) is caused by a CAG, CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGlnexpansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other polyglutamine diseases.

引用

页码：667 / 677

页数：11

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