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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
Summary
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.
- 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.