title: Rapid Onset of Motor Deficits in a Mouse Model of Spinocerebellar Ataxia Type 6 Precedes Late Cerebellar Degeneration.
abstract: Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells. Disease onset is typically at midlife, although it can vary widely from late teens to old age in SCA6 patients. Our study focused on an SCA6 knock-in mouse model with a hyper-expanded (84X) CAG repeat expansion that displays midlife-onset motor deficits at ∼7 months old, reminiscent of midlife-onset symptoms in SCA6 patients, although a detailed phenotypic analysis of these mice has not yet been reported. Here, we characterize the onset of motor deficits in SCA6(84Q) mice using a battery of behavioral assays to test for impairments in motor coordination, balance, and gait. We found that these mice performed normally on these assays up to and including at 6 months, but motor impairment was detected at 7 months with all motor coordination assays used, suggesting that motor deficits emerge rapidly during a narrow age window in SCA6(84Q) mice. In contrast to what is seen in SCA6 patients, the decrease in motor coordination was observed without alterations in gait. No loss of cerebellar Purkinje cells or striatal neurons were observed at 7 months, the age at which motor deficits were first detected, but significant Purkinje cell loss was observed in 2-year-old SCA6(84Q) mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6.
authors.affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.
authors.forename: Sriram
authors.identifier: 0000-0002-0485-6725
authors.initials: S
authors.lastname: Jayabal
authors.affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.
authors.forename: Lovisa
authors.initials: L
authors.lastname: Ljungberg
authors.affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.
authors.forename: Thomas
authors.identifier: 0000-0001-7809-4703
authors.initials: T
authors.lastname: Erwes
authors.affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Cormier
authors.affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Quilez
authors.affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.
authors.forename: Sara
authors.identifier: 0000-0002-3765-8290
authors.initials: S
authors.lastname: El Jaouhari
authors.affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.
authors.forename: Alanna J
authors.identifier: 0000-0002-6371-6220
authors.initials: AJ
authors.lastname: Watt
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D011689:Purkinje Cells / Q000166:cytology*; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology; D013997:Time Factors
chemical_list: D015220:Calcium Channels
keywords: Purkinje cell; ataxia: behavioral assays; cerebellum; neurodegeneration