Spinocerebellar Ataxia Type 6 Protein Aggregates Cause Deficits in Motor Learning and Cerebellar Plasticity

Abstract

Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca 2ϩ channels (Ca v 2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that a CT fragment of the Ca v 2.1 channel, which is detected specifically in cytosolic and nuclear fractions in SCA6 patients, is associated with the SCA6 pathogenesis. To test this hypothesis, we expressed P/Q-type channel protein fragments from two different human CT splice variants, as predicted from SCA6 patients, in PCs of mice using viral and transgenic approaches. These splice variants represent a short (CT-short without polyQs) and a long (CT-long with 27 polyQs) CT fragment. Our results show that the different splice variants of the CTs differentially distribute within PCs, i.e., the short CTs reveal predominantly nuclear inclusions, whereas the long CTs prominently reveal both nuclear and cytoplasmic aggregates. Postnatal expression of CTs in PCs in mice reveals that only CT-long causes SCA6-like symptoms, i.e., deficits in eyeblink conditioning (EBC), ataxia, and PC degeneration. The physiological phenotypes associated specifically with the long CT fragment can be explained by an impairment of LTD and LTP at the parallel fiber-to-PC synapse and alteration in spontaneous PC activity. Thus, our results suggest that the polyQ carrying the CT fragment of the P/Q-type channel is sufficient to cause SCA6 pathogenesis in mice and identifies EBC as a new diagnostic strategy to evaluate Ca 2ϩ channel-mediated human diseases.

Transient cerebellar alterations during development prior to obvious motor phenotype in a mouse model of spinocerebellar ataxia type 6

“…), and during later stages of disease in a separate SCA6 mouse model (Mark et al . ). To address whether Purkinje cell firing properties were affected during development, we recorded extracellular spontaneous Purkinje cell activity in acute sagittal cerebellar slices from P10–13 WT and SCA6 84Q/84Q mice, since the cerebellar circuit at this age is still undergoing profound developmental changes (McKay & Turner, ; van Welie et al .…”

“…), or in a separate SCA6 model when ataxia was present (Mark et al . ). Interestingly, the CV was not found to be significantly different between SCA6 84Q/84Q and WT Purkinje cells (WT: CV = 0.25 ± 0.02, n = 33; SCA6 84Q/84Q : CV = 0.21 ± 0.01, n = 34, not significantly different from WT, P = 0.09).…”

“…; Mark et al . ) where it may act as a transcriptional regulator and influence cerebellar development (Du et al . ).…”

“…; Mark et al . ), although disease onset precedes Purkinje cell loss in some mouse models (Unno et al . ; Jayabal et al .…”

Cellular and circuit mechanisms underlying spinocerebellar ataxias

“…Lastly, a PN‐specific SCA6 transgenic mouse line expressing a C‐terminal fragment, corresponding to exon 47, of the P‐type Ca 2+ channel containing 27 polyglutamine repeats has been characterized (Mark et al . ). PN firing rates in this mouse are reduced and firing becomes markedly irregular.…”