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Related Experiment Videos

Mutant Huntingtin Disrupts the Nuclear Pore Complex.

Jonathan C Grima1, J Gavin Daigle2, Nicolas Arbez3

  • 1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Neuron
|April 7, 2017
PubMed

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Summary
This summary is machine-generated.

Huntington's disease involves defects in nuclear pore complex (NPC) protein transport. Targeting these nucleoporins (NUPs) and their biology may offer new therapeutic strategies for this neurodegenerative disorder.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) is a genetic neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin (HTT) gene.
  • The precise mechanisms by which mutant Huntingtin (mHTT) leads to neurodegeneration remain incompletely understood.
  • Nucleocytoplasmic transport, regulated by nuclear pore complexes (NPCs) composed of nucleoporins (NUPs), is crucial for cellular function.

Purpose of the Study:

  • To investigate the role of nucleocytoplasmic transport and NPC integrity in Huntington's disease pathogenesis.
  • To evaluate the impact of mHTT on NUPs and nucleocytoplasmic transport across various HD models.

Main Methods:

  • Utilized multiple models of HD, including mouse and fly models, mHTT-transfected neurons, HD induced pluripotent stem cell (iPSC)-derived neurons, and human HD brain tissue.
Keywords:
C9ORF72Huntington’s diseaseKPT-350O-GlcNAcRAN translationThiamet-Ginduced pluripotent stem cellneurodegenerationnuclear pore complexnucleocytoplasmic transport

Related Experiment Videos

  • Assessed NUP localization, NPC function, and nucleocytoplasmic transport efficiency.
  • Investigated the role of HD repeat-associated non-ATG (RAN) translation products.

    • Main Results:

    • Demonstrated significant NUP mislocalization and aggregation in all evaluated HD models.
    • Confirmed defective nucleocytoplasmic transport associated with mHTT expression.
    • Identified HD-associated RAN translation proteins as contributors to transport defects.

    Conclusions:

    • Mutant HTT disrupts NPC structure and function, leading to impaired nucleocytoplasmic transport in Huntington's disease.
    • Overexpression of NUPs or pharmacological interventions targeting aberrant NUP biology ameliorated transport defects and neurotoxicity.
    • These findings highlight NPCs and nucleocytoplasmic transport as promising therapeutic targets for HD.