Neuron
Volume 94, Issue 1, 5 April 2017, Pages 93-107.e6
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Article
Mutant Huntingtin Disrupts the Nuclear Pore Complex

https://doi.org/10.1016/j.neuron.2017.03.023Get rights and content
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Highlights

  • HD human and mouse brain share profound nuclear pore complex pathology

  • HD iPS neurons mirror dysregulated HD human brain nuclear pore complex pathology

  • Aberrant nucleocytoplasmic transport is identified in various in vitro HD models

  • HD neurotoxicity can be mitigated with rescue of nucleocytoplasmic transport defects

Summary

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.

Keywords

Huntington’s disease
C9ORF72
neurodegeneration
nucleocytoplasmic transport
nuclear pore complex
RAN translation
induced pluripotent stem cell
O-GlcNAc
Thiamet-G
KPT-350

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