title: Early autophagic response in a novel knock-in model of Huntington disease.
abstract: 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 approximately 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.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Mary Y
authors.initials: MY
authors.lastname: Heng
authors.forename: Duy K
authors.initials: DK
authors.lastname: Duong
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Tallaksen-Greene
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Hunter
authors.forename: Mathieu J
authors.initials: MJ
authors.lastname: Lesort
authors.forename: Alex
authors.initials: A
authors.lastname: Osmand
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Detloff
mesh_terms: D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006262:Health; D006579:Heterozygote; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity; D009154:Mutation / Q000235:genetics; D017072:Neostriatum / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D011954:Receptors, Dopamine / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D011954:Receptors, Dopamine; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D025801:Ubiquitin