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Updated: Apr 17, 2026
Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
N17 Modifies mutant Huntingtin nuclear pathogenesis and severity of disease in HD BAC transgenic mice
Xiaofeng Gu1, Jeffrey P Cantle1, Erin R Greiner2
1Center 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.
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.
