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 Lloyd, Christopher A Ross, Jeffrey D Rothstein

Research output: Contribution to journalArticle

Abstract

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 (US)
Pages (from-to)93-107.e6
JournalNeuron
Volume94
Issue number1
DOIs
StatePublished - Apr 5 2017

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Grima, J. C., Daigle, J. G., Arbez, N., Cunningham, K. C., Zhang, K., Ochaba, J., Geater, C., Morozko, E., Stocksdale, J., Glatzer, J. C., Pham, J. T., Ahmed, I., Peng, Q., Wadhwa, H., Pletnikova, O., Troncoso, J. C., Duan, W., Snyder, S. H., Ranum, L. P. W., ... Rothstein, J. D. (2017). Mutant Huntingtin Disrupts the Nuclear Pore Complex. Neuron, 94(1), 93-107.e6. https://doi.org/10.1016/j.neuron.2017.03.023