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

Gu, X. and Cantle, J. P. and Greiner, E. R. and Lee, C. Y. and Barth, Albert (2015) N17 Modifies mutant Huntingtin nuclear pathogenesis and severity of disease in HD BAC transgenic mice. NEURON, 85 (4). pp. 726-741. ISSN 0896-6273

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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-DeltaN17) show dramatically accelerated mHTT pathology exclusively in the nucleus, which is associated with HD-like transcriptionopathy. Interestingly, BACHD-DeltaN17 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.

Item Type: Article
Uncontrolled Keywords: Trinucleotide Repeat Expansion/*genetics; Subcellular Fractions/metabolism/pathology; Protein Structure, Tertiary/genetics; PHENOTYPE; Organ Size/genetics; Nuclear Proteins/*genetics; Neurons/metabolism/pathology; Nerve Tissue Proteins/*genetics/metabolism; Mice, Transgenic; MICE; Male; Locomotion/genetics; Huntington Disease/complications/*genetics/*pathology; Humans; HEK293 Cells/ultrastructure; Gene Expression Regulation/genetics; Female; Disease Models, Animal; Cell Nucleolus/*metabolism/pathology; Brain/metabolism/pathology; Animals; Age Factors
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
Q Science / természettudomány > QH Natural history / természetrajz > QH426 Genetics / genetika, örökléstan
R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan, neurológia, pszichiátria
Depositing User: MTMT SWORD
Date Deposited: 04 May 2016 12:01
Last Modified: 04 May 2016 12:01

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