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Rapid Onset of Motor Deficits in a Mouse Model of Spinocerebellar Ataxia Type 6 Precedes Late Cerebellar Degeneration.

Jayabal S, Ljungberg L, Erwes T, Cormier A, Quilez S, El Jaouhari S, Watt AJ - eNeuro (2015)

Bottom Line: Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.

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.

No MeSH data available.


Related in: MedlinePlus

No loss of striatal neurons in SCA684Q/84Q mice accompanies the onset of motor coordination deficits at 7 months. A, Representative images of NeuN-stained cells from 7-month-old WT (left) and SCA684Q/84Q (right) mouse striatum. Scale bar, 20 μm. B, Density of striatal cells is not significantly different in SCA684Q/84Q compared with WT mice at 7 months (Student’s t test, p = 0.72).
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Figure 8: No loss of striatal neurons in SCA684Q/84Q mice accompanies the onset of motor coordination deficits at 7 months. A, Representative images of NeuN-stained cells from 7-month-old WT (left) and SCA684Q/84Q (right) mouse striatum. Scale bar, 20 μm. B, Density of striatal cells is not significantly different in SCA684Q/84Q compared with WT mice at 7 months (Student’s t test, p = 0.72).

Mentions: Although SCA6 has been considered to be an example of a pure cerebellar ataxia (Solodkin and Gomez, 2012), noncerebellar symptoms are present in some patients, with up to 25% of affected individuals having signs of basal ganglia-related symptoms (Solodkin and Gomez, 2012). Since several recent studies have reported degeneration in the striatum of patients with other SCAs, including SCA2 and SCA3 (Schöls et al., 2015), and SCA17 (Brockmann et al., 2012), we looked at the number of striatal neurons in SCA684Q/84Q mice at 7 months to determine whether degeneration in the striatum was associated with the onset of motor abnormalities. We found that there were no significant differences between the density of cells in the striatum of SCA684Q/84Q and WT mice at 7 months (SCA684Q/84Q mice: 1191 ± 36 cells/mm2 striatum, total of 3332 cells counted from N = 4 mice; WT mice: 1212 ± 48 cells/mm2, total of 2586 cells counted from N = 3 mice; not significantly different, p = 0.72; Fig. 8).


Rapid Onset of Motor Deficits in a Mouse Model of Spinocerebellar Ataxia Type 6 Precedes Late Cerebellar Degeneration.

Jayabal S, Ljungberg L, Erwes T, Cormier A, Quilez S, El Jaouhari S, Watt AJ - eNeuro (2015)

No loss of striatal neurons in SCA684Q/84Q mice accompanies the onset of motor coordination deficits at 7 months. A, Representative images of NeuN-stained cells from 7-month-old WT (left) and SCA684Q/84Q (right) mouse striatum. Scale bar, 20 μm. B, Density of striatal cells is not significantly different in SCA684Q/84Q compared with WT mice at 7 months (Student’s t test, p = 0.72).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697081&req=5

Figure 8: No loss of striatal neurons in SCA684Q/84Q mice accompanies the onset of motor coordination deficits at 7 months. A, Representative images of NeuN-stained cells from 7-month-old WT (left) and SCA684Q/84Q (right) mouse striatum. Scale bar, 20 μm. B, Density of striatal cells is not significantly different in SCA684Q/84Q compared with WT mice at 7 months (Student’s t test, p = 0.72).
Mentions: Although SCA6 has been considered to be an example of a pure cerebellar ataxia (Solodkin and Gomez, 2012), noncerebellar symptoms are present in some patients, with up to 25% of affected individuals having signs of basal ganglia-related symptoms (Solodkin and Gomez, 2012). Since several recent studies have reported degeneration in the striatum of patients with other SCAs, including SCA2 and SCA3 (Schöls et al., 2015), and SCA17 (Brockmann et al., 2012), we looked at the number of striatal neurons in SCA684Q/84Q mice at 7 months to determine whether degeneration in the striatum was associated with the onset of motor abnormalities. We found that there were no significant differences between the density of cells in the striatum of SCA684Q/84Q and WT mice at 7 months (SCA684Q/84Q mice: 1191 ± 36 cells/mm2 striatum, total of 3332 cells counted from N = 4 mice; WT mice: 1212 ± 48 cells/mm2, total of 2586 cells counted from N = 3 mice; not significantly different, p = 0.72; Fig. 8).

Bottom Line: Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, McGill University , Montreal, Quebec, Canada.

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.

No MeSH data available.


Related in: MedlinePlus