Mutant Huntingtin Disrupts the Nuclear Pore Complex

被引：262

作者：

Grima, Jonathan C. ^{[1
,2
,3
]}

Daigle, J. Gavin ^{[2
,3
]}

Arbez, Nicolas ^{[1
,5
]}

Cunningham, Kathleen C. ^{[3
,4
]}

Zhang, Ke ^{[2
,3
]}

Ochaba, Joseph ^{[7
]}

Geater, Charlene ^{[7
]}

Morozko, Eva ^{[7
]}

Stocksdale, Jennifer ^{[7
]}

Glatzer, Jenna C. ^{[2
,3
]}

Pham, Jacqueline T. ^{[2
,4
]}

Ahmed, Ishrat ^{[1
]}

Peng, Qi ^{[1
]}

Wadhwa, Harsh ^{[3
]}

Pletnikova, Olga ^{[6
]}

Troncoso, Juan C. ^{[3
,6
]}

Duan, Wenzhen ^{[1
,4
,5
]}

Snyder, Solomon H. ^{[1
,5
]}

Ranum, Laura P. W. ^{[8
,9
]}

Thompson, Leslie M. ^{[7
]}

Lloyd, Thomas E. ^{[1
,2
,3
,4
]}

Ross, Christopher A. ^{[1
,5
]}

Rothstein, Jeffrey D. ^{[1
,2
,3
,4
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Brain Sci Inst, Baltimore, MD 21205 USA

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

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

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

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

[7] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA

[8] Univ Florida, Ctr NeuroGenet, Coll Med, Dept Mol Genet & Microbiol,Genet Inst,McKnight Br, Gainesville, FL 32611 USA

[9] Univ Florida, Ctr NeuroGenet, Coll Med, Dept Neurol,Genet Inst,McKnight Brain Inst, Gainesville, FL 32611 USA

来源：

NEURON | 2017年 / 94卷 / 01期

基金：

美国国家科学基金会;

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; NUCLEOCYTOPLASMIC TRANSPORT; REPEAT EXPANSION; O-GLCNACYLATION; ALZHEIMER-DISEASE; RESPONSE ELEMENT; PROTEINS; EXPRESSION; EXPORT; METABOLISM;

D O I：

10.1016/j.neuron.2017.03.023

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons, and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective nucleocytoplasmic transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted nucleocytoplasmic transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this transport defect and neurotoxicity, providing future novel therapy targets.

引用

页码：93 / +

页数：21

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