title: Differential effects of delayed aging on phenotype and striatal pathology in a murine model of Huntington disease.
abstract: The common neurodegenerative syndromes exhibit age-related incidence, and many Mendelian neurodegenerative diseases exhibit age-related penetrance. Mutations slowing aging retard age related pathologies. To assess whether delayed aging retards the effects of a mutant allele causing a Huntington's disease (HD)-like syndrome, we generated compound mutant mice, placing a dominant HD knock-in polyglutamine allele onto the slow-aging Snell dwarf genotype. The Snell genotype did not affect mutant huntingtin protein expression. Bigenic and control mice were evaluated prospectively from 10 to 100 weeks of age. Adult HD knock-in allele mice lost weight progressively with weight loss blunted significantly in male bigenic HD knock-in/Snell dwarf mice. Impaired balance beam performance developed significantly more slowly in bigenic HD knock-in/Snell dwarf mice. Striatal dopamine receptor expression was diminished significantly and similarly in all HD-like mice, regardless of the Snell genotype. Striatal neuronal intranuclear inclusion burden was similar between HD knock-in mice with and without the Snell genotype, whereas nigral neuropil aggregates were diminished in bigenic HD knock-in/Snell dwarf mice. Compared with control mice, Snell dwarf mice exhibited differences in regional benzodiazepine and cannabinoid receptor binding site expression. These results indicate that delaying aging delayed behavioral decline with little effect on the development of striatal pathology in this model of HD but may have altered synaptic pathology. These results indicate that mutations prolonging lifespan in mice delay onset of significant phenotypic features of this model and also demonstrate dissociation between striatal pathology and a commonly used behavioral measure of disease burden in HD models.
authors.affiliation: Departments of Neurology.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Tallaksen-Greene
authors.affiliation: Internal Medicine.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sadagurski
authors.affiliation: Departments of Neurology.
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Departments of Neurology.
authors.forename: Roseanne
authors.initials: R
authors.lastname: Mauch
authors.affiliation: Departments of Neurology.
authors.forename: Matthew
authors.initials: M
authors.lastname: Perkins
authors.affiliation: Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Varuna C
authors.initials: VC
authors.lastname: Banduseela
authors.affiliation: Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.affiliation: Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: Departments of Neurology, Michigan Alzheimer Disease Center, Ann Arbor, Michigan 48105, and.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
authors.affiliation: Departments of Neurology, Michigan Alzheimer Disease Center, Ann Arbor, Michigan 48105, and Neurology Service and Geriatrics Research, Education, and Clinical Center, VAAAHS, Ann Arbor, Michigan 48105 ralbin@umich.edu.
authors.forename: Roger L
authors.identifier: http://orcid.org/0000-0002-0629-608X
authors.initials: RL
authors.lastname: Albin
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006816:Huntington Disease / Q000473:pathology* / Q000523:psychology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology; D017072:Neostriatum / Q000473:pathology*; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D047495:PPAR gamma
keywords: aging; neurodegeneration; polyglutamine; striatum