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

• Published in: Human molecular genetics Vol. 19; no. 19; pp. 3702 - 3720
• Main Authors: Heng, Mary Y., Duong, Duy K., Albin, Roger L., Tallaksen-Greene, Sara J., Hunter, Jesse M., Lesort, Mathieu J., Osmand, Alex, Paulson, Henry L., Detloff, Peter J.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.2010
• Subjects: Animals; Autophagy; Biological and medical sciences; Biomarkers - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Gene Knock-In Techniques; Genetics of eukaryotes. Biological and molecular evolution; Glial Fibrillary Acidic Protein - metabolism; Health; Heterozygote; Huntington Disease - genetics; Huntington Disease - pathology; Huntington Disease - physiopathology; Medical sciences; Mice; Microtubule-Associated Proteins - metabolism; Molecular and cellular biology; Motor Activity; Mutation - genetics; Neostriatum - pathology; Neostriatum - physiopathology; Neostriatum - ultrastructure; Neurology; Neurons - pathology; Neurons - ultrastructure; Protein Structure, Quaternary; Protein Transport; Receptors, Dopamine - metabolism; Serotonin Plasma Membrane Transport Proteins - chemistry; Serotonin Plasma Membrane Transport Proteins - genetics; Ubiquitin - metabolism; Nervous system diseases; Huntingtin; Central nervous system disease; Huntington disease; Genetics; Early; Degenerative disease; Models; Genetic disease; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq285

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.