期刊
NEURON
卷 94, 期 1, 页码 93-+出版社
CELL PRESS
DOI: 10.1016/j.neuron.2017.03.023
关键词
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资金
- NIH [R01NS094239, R01NS085207]
- National Science Foundation
- Thomas Shortman Training Fund Graduate Award
- Axol Science Award
- NIH Training in Neurotherapeutics Discovery and Development for Academic Scientists
- MDI Biological Laboratory QFM Chroma Fellowship Award
- CIRM Training Grant
- Johns Hopkins Brain Science Institute
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.
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