Journal Article

Early autophagic response in a novel knock-in model of Huntington disease

Mary Y. Heng, Duy K. Duong, Roger L. Albin, Sara J. Tallaksen-Greene, Jesse M. Hunter, Mathieu J. Lesort, Alex Osmand, Henry L. Paulson and Peter J. Detloff

in Human Molecular Genetics

Volume 19, issue 19, pages 3702-3720
Published in print October 2010 | ISSN: 0964-6906
Published online July 2010 | e-ISSN: 1460-2083 | DOI:
Early autophagic response in a novel knock-in model of Huntington disease

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The aggregation of mutant polyglutamine (polyQ) proteins has sparked interest in the role of protein quality-control pathways in Huntington's disease (HD) and related polyQ disorders. Employing a novel knock-in HD mouse model, we provide in vivo evidence of early, sustained alterations of autophagy in response to mutant huntingtin (mhtt). The HdhQ200 knock-in model, derived from the selective breeding of HdhQ150 knock-in mice, manifests an accelerated and more robust phenotype than the parent line. Heterozygous HdhQ200 mice accumulate htt aggregates as cytoplasmic aggregation foci (AF) as early as 9 weeks of age and striatal neuronal intranuclear inclusions (NIIs) by 20 weeks. By 40 weeks, striatal AF are perinuclear and immunoreactive for ubiquitin and the autophagosome marker LC3. Striatal NIIs accumulate earlier in HdhQ200 mice than in HdhQ150 mice. The earlier appearance of aggregate pathology in HdhQ200 mice is paralleled by earlier and more rapidly progressive motor deficits: progressive imbalance and decreased motor coordination by 50 weeks, gait deficits by 60 weeks and gross motor impairment by 80 weeks of age. At 80 weeks, heterozygous HdhQ200 mice exhibit striatal and cortical astrogliosis and a ∼50% reduction in striatal dopamine receptor binding. Increased LC3-II protein expression, which is noted early and sustained throughout the disease course, is paralleled by increased expression of the autophagy-related protein, p62. Early and sustained expression of autophagy-related proteins in this genetically precise mouse model of HD suggests that the alteration of autophagic flux is an important and early component of the neuronal response to mhtt.

Journal Article.  10222 words.  Illustrated.

Subjects: Genetics and Genomics

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