N17 Modifies mutant Huntingtin nuclear pathogenesis and severity of disease in HD BAC transgenic mice

Xiaofeng Gu; Jeffrey P Cantle; Erin R Greiner; C Y Daniel Lee; Albert M Barth; Fuying Gao; Chang Sin Park; Zhiqiang Zhang; Susana Sandoval-Miller; Richard L Zhang; Marc Diamond; Istvan Mody; Giovanni Coppola; X William Yang

doi:10.1016/j.neuron.2015.01.008

N17 Modifies mutant Huntingtin nuclear pathogenesis and severity of disease in HD BAC transgenic mice

Neuron. 2015 Feb 18;85(4):726-41. doi: 10.1016/j.neuron.2015.01.008. Epub 2015 Feb 5.

Authors

Affiliations

¹ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Neurology, Washington University School of Medicine St. Louis, MO 63110, USA; Department of Neurology and Neurotherapeutics, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].

Abstract

The nucleus is a critical subcellular compartment for the pathogenesis of polyglutamine disorders, including Huntington's disease (HD). Recent studies suggest the first 17-amino-acid domain (N17) of mutant huntingtin (mHTT) mediates its nuclear exclusion in cultured cells. Here, we test whether N17 could be a molecular determinant of nuclear mHTT pathogenesis in vivo. BAC transgenic mice expressing mHTT lacking the N17 domain (BACHD-ΔN17) show dramatically accelerated mHTT pathology exclusively in the nucleus, which is associated with HD-like transcriptionopathy. Interestingly, BACHD-ΔN17 mice manifest more overt disease-like phenotypes than the original BACHD mice, including body weight loss, movement deficits, robust striatal neuron loss, and neuroinflammation. Mechanistically, N17 is necessary for nuclear exclusion of small mHTT fragments that are part of nuclear pathology in HD. Together, our study suggests that N17 modifies nuclear pathogenesis and disease severity in HD mice by regulating subcellular localization of known nuclear pathogenic mHTT species.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Age Factors
Animals
Brain / metabolism
Brain / pathology
Cell Nucleolus / metabolism*
Cell Nucleolus / pathology
Disease Models, Animal
Female
Gene Expression Regulation / genetics
HEK293 Cells / ultrastructure
Humans
Huntingtin Protein
Huntington Disease / complications
Huntington Disease / genetics*
Huntington Disease / pathology*
Locomotion / genetics
Male
Mice
Mice, Transgenic
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Neurons / metabolism
Neurons / pathology
Nuclear Proteins / genetics*
Organ Size / genetics
Phenotype
Protein Structure, Tertiary / genetics
Subcellular Fractions / metabolism
Subcellular Fractions / pathology
Trinucleotide Repeat Expansion / genetics*

N17 Modifies mutant Huntingtin nuclear pathogenesis and severity of disease in HD BAC transgenic mice

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