Longitudinal analysis of motor symptoms and histopathology in woozy mice, a model of cerebellar ataxia

Abstract

Woozy (wz) mice develop ataxia and carry a mutation in the Sil1 gene. Homozygous wz mice have been characterized histopathologically, but no details of their motor function have been reported. In the present study, to comprehensively understand the relationship between symptomatic progression and pathological feature, we evaluated motor function and neurodegeneration with age from presymptomatic to terminal stages. We evaluated the motor function of homozygous and heterozygous wz mice aged from 5 to 71 weeks. Motor function was evaluated using the rotarod test, the footprint test, and the parallel rod floor test. Furthermore, we carried out a histopathological analysis of the mice at several ages. Impairment of motor function in homozygous wz mice began at around 11 weeks of age and became markedly worse until around 14 weeks. Heterozygous wz mice did not show motor dysfunction until 71 weeks of age. Features of cerebellar ataxia were evaluated using the footprint test and the parallel rod floor test. In addition to the observation of ubiquitin-positive aggregates at 6 weeks of age, Purkinje cell loss at 9 weeks of age and cerebellar atrophy were confirmed by histopathology. Apart from the cerebellar changes, we detected no other pathology that could contribute toward ataxia. In heterozygous wz mice, only minimal formation of ubiquitin-positive aggregates was observed. Homozygous wz mice showed adult-onset ataxia with progressive neurodegeneration of the cerebellum. Homozygous wz mice might be useful as an animal model of diseases showing adult-onset ataxia because of cerebellar neurodegeneration.

Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice

“…1). Since we and others found no significant differences in motor performance and cerebellar anatomy between wild-type and heterozygous mice (6,11,17), we used heterozygous littermates of woozy mice as controls (referred to here as WT). No sex-related differences were observed in the woozy phenotype (11,17), so both male and female mice were included.…”

“…CHO-KI CHOP::luciferase cells (17) (a gift from David Ron, Cambridge University, UK) were cultured in Dulbecco’s modified Eagle medium (DMEM)/F12(Ham) (Gibco) supplemented with 10% fetal bovine serum (Sigma Aldrich), 2 mM L-glutamine (Merck Millipore) and 1% penicillin/streptomycin (Merck Millipore) with 200 μg/mL G418 (Life Technologies). HEK293 cells were cultured in DMEM (Merck Millipore) supplemented with 10% fetal bovine serum, 2 mM L-glutamine and 1% penicillin/streptomycin.…”

“…CHO-KI cells stably transfected with CHOP::luciferase reporter (17) were cultured as described above: 0.6 x 10 5 cells/cm 2 were plated in a 96-well plate and left growing for 24h. Cells were exposed to 3 μg/mL of tunicamycin or vehicle (dimethylsulphoxide, DMSO, Sigma), and treated for 6h with pharmacological compounds at concentrations ranging from 0.1 to 500 μM.…”

Selection for Divergent Reproductive Investment Affects Neuron Size and Foliation in the Cerebellum

“…In mutant strains of lab mice (Mus musculus), such as lurcher, woozy, and Purkinje cell deterioration (pcd), a reduction in cerebellum size and foliation is often due to neuron loss [Vogel et al, 1989;Wang and Morgan, 2007;Hayashi et al, 2017]. However, all 3 of these strains, and others that experience Purkinje cell loss, are characterized by ataxic gaits and significantly impaired motor performance on a variety of tasks [Lalonde and Strazielle, 2001;Hayashi et al, 2017], so they are unlikely to represent natural variation in animal populations. Further, the relationship between cerebellar foliation and motor performance across mouse strains is currently unclear [Le Roy-Duflos, 2001], and data on cerebellar neuron numbers or sizes within and across mouse strains is wanting.…”

“…Alternatively, the size difference could arise primarily from a change in a specific layer or neuronal population within the cerebellum. For example, Purkinje cell loss is one of the mechanisms that contributes to decreases in cerebellar size and foliation in mutant mice [Vogel et al, 1989;Wang and Morgan, 2007;Hayashi et al, 2017]. Changes in Purkinje cell sizes or numbers could also contribute to cerebellar size in quail without affecting the sizes of the molecular or granule cell layers.…”