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Neuron. 2017 Apr 5;94(1):93-107.e6. doi: 10.1016/j.neuron.2017.03.023.

Mutant Huntingtin Disrupts the Nuclear Pore Complex.

Author information

1
Solomon 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.
2
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.
3
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
6
Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
9
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12
Center for NeuroGenetics, Departments of Molecular Genetics and Microbiology and Neurology, College of Medicine, Genetics Institute, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
13
Solomon 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; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
14
Solomon 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; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jrothstein@jhmi.edu.

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.

KEYWORDS:

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

PMID:
28384479
PMCID:
PMC5595097
DOI:
10.1016/j.neuron.2017.03.023
[Indexed for MEDLINE]
Free PMC Article

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