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 SCA684Q 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 SCA684Q 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 SCA684Q mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6.

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

“…We used SCA6 84Q/84Q mice harboring an expanded polyglutamine (poly-Q) repeat which have been shown to display ataxic symptoms at 7 months old (Watase et al, 2008; Jayabal et al, 2015). We have previously shown that there is no Purkinje cell loss at 7 months when disease symptoms are first observed, although Purkinje cell loss is detectable at 2 years (Jayabal et al, 2015). We first wondered whether disease-related torpedoes would be observed in these mice at 2 years.…”

“…We found, however, that developmental torpedo density was normal in P11 SCA6 84Q/84Q mice compared to WT, suggesting that they are not directly related to later pathophysiology (P11 WT: 2.71 ± 0.90 torpedoes/section; P11 SCA6 84Q/84Q : 2.61 ± 0.54 torpedoes/section; not significantly different, P = 0.92; Figure 8B , left). We also measured the density of Purkinje cell torpedoes in SCA6 84Q/84Q and litter-matched mice at 7 months, when cerebellar-related motor deficits are observed without detectable Purkinje cell loss (Jayabal et al, 2015, 2016a), and found that torpedo density was low at 7 months and similar in both WT and SCA6 84Q/84Q mice (7 month WT: 0.57 ± 0.20 torpedoes/section; 7 month SCA6 84Q/84Q : 0.42 ± 0.13 torpedoes/section; not significantly different; P = 0.53; Figure 8B , middle). Note that we observe higher torpedo numbers in P11 mice than 7-month-old mice in both WT and SCA6 84Q/84Q mice, which is consistent with our observations of a transient developmental peak of torpedoes at P11 ( Figure 1 ).…”

“…Scale bar, 20 μm. (B) Although the number of Purkinje cell axonal torpedoes are high in SCA6 84Q/84Q mice (purple) compared to WT mice (white bars) at an age when Purkinje cell death is observed (right) (Jayabal et al, 2015), there are no statistically significant differences in the number of torpedoes observed during development at P11 in these mice (left), and torpedo numbers are low in 7-month-old mice when disease symptoms first appear (middle) (Jayabal et al, 2015). These results suggest that developmental torpedoes are not directly related to disease-related torpedoes, as they appear at normal levels in late-onset disease models.…”

“…We used a mouse model of SCA6 that we have previously characterized in our lab to address this. These mice show initial motor symptoms at 7 months, which progressively worsen (Jayabal et al, 2015). Purkinje cell death is not observed at 7 months, but is seen at 2-years-old (Jayabal et al, 2015).…”

“…These mice show initial motor symptoms at 7 months, which progressively worsen (Jayabal et al, 2015). Purkinje cell death is not observed at 7 months, but is seen at 2-years-old (Jayabal et al, 2015). We found that although disease-related torpedoes were highly enriched in 2-year-old mice when Purkinje cell death was observed, there were no differences in torpedo numbers at P11, suggesting that developmental torpedoes are not related to later disease-onset torpedoes.…”