Pathogenic mechanism of calcium channelopathy

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Spinocerebellar ataxia type 6 (SCA6) is caused by polyglutamine expansion in P-type Ca channel and is characterized by predominant degeneration of cerebellar Purkinje cell. Although clinical and pathological features of each polyglutamine disease diverse widely, a common mechanism is presumed to underlie the pathogenesis inducing cytotoxicity. Polyglutamine expansion in SCA6 is within the normal range in other disease. Thus a different idea that functional alteration of the P-type Ca channel is causally related to pathophysiology of SCA6 has been emerged. Consistent with this idea several reports have been published showing SCA6 mutation induces alteration of channel properties. But these studies have been done using the non-neuronal cells. To characterize SCA6 mutation of P-type Ca channel in neuron especially in Purkinje cells, we have generated knock-in mouse models that express human P-type Ca^<2+> channel with SCA6 mutation. Patch-clamp recordings of the Purkinje cells from homozygous normal or SCA6 knock-in mice showed no alteration of channel properties by the SCA6 mutation. Thus SCA6 has been considered as one of channelopathies rather than a polyglutamine disease, our present results favors the idea that SCA6 is rather a polyglutamine disease. Therefore it may be important to explore the mechanism underlying SCA6 from the point of view of polyglutamine disease.In line with this consideration, we have tested whether SCA6 mutation affects the channel localization. When using the primary cultured hippocampal neurons, SCA6 mutation did not modify the channel localization. Then we are currently conducting this study using cerebellar Purkinje cells.