Mutant Huntingtin Disrupts the Nuclear Pore Complex

Jonathan C. Grima, J. Gavin Daigle, Nicolas Arbez, Kathleen C. Cunningham, Ke Zhang, Joseph Ochaba, Charlene Geater, Eva Morozko, Jennifer Stocksdale, Jenna C. Glatzer, Jacqueline T. Pham, Ishrat Ahmed, Qi Peng, Harsh Wadhwa, Olga Pletnikova, Juan C. Troncoso, Wenzhen Duan, Solomon H. Snyder, Laura P.W. Ranum, Leslie M. ThompsonThomas E. Lloyd, Christopher A. Ross, Jeffrey D. Rothstein

Research output: Contribution to journalArticlepeer-review

242 Scopus citations


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.

Original languageEnglish
Pages (from-to)93-107.e6
Issue number1
StatePublished - 5 Apr 2017
Externally publishedYes


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


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