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

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

The nucleus is a critical subcellular compartment forthe 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 invivo. BAC transgenic mice expressing mHTT lacking the N17 domain (BACHD-δN17) show dramatically accelerated mHTT pathology exclusively in the nucleus, which is associatedwith 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 subcellularlocalization of known nuclear pathogenic mHTT species.

Original languageEnglish (US)
Pages (from-to)726-741
Number of pages16
JournalNeuron
Volume85
Issue number4
DOIs
StatePublished - Feb 18 2015

ASJC Scopus subject areas

  • Neuroscience(all)

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    Gu, X., Cantle, J. P., Greiner, E. R., Lee, C. Y. D., Barth, A. M., Gao, F., Park, C. S., Zhang, Z., Sandoval-Miller, S., Zhang, R. L., Diamond, M., Mody, I., Coppola, G., & Yang, X. W. (2015). N17 Modifies Mutant Huntingtin Nuclear Pathogenesis and Severity of Disease in HD BAC Transgenic Mice. Neuron, 85(4), 726-741. https://doi.org/10.1016/j.neuron.2015.01.008