Molecular physiopathology of the spinocerebellar ataxia type 6 (SCA6)

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative, monogenic, and autosomic dominant disease which is characterized by a global cerebellar atrophy. Typically the onset is at mature age and undergoes a moderate evolution. This illness has been associated with a mutation in the gene CACNA1A, that encodes for subunit alpha(1A) of P/Q type voltage/dependent calcium channel. The mutation results in the expansion of a CAG triplet repeat located in the last exon of the gene, which is translated into a polyglutamine chain in the carboxyl tail of the calcium channel subunit. Several studies have been made to clarify the mechanism for the toxicity of polyglutamines in cerebellar neurons; SCA6 could be considered a polyglutamine proteinopathy linked to caspases mediated death pathway. However, SCA6 is also considered a channelopathy, like paroxysmal diseases as hemiplegic familiar migraine and episodic ataxia type 2. The goal of this review is to analyze the intracellular mechanism triggering neuronal death in cerebellum, and the subsequent neurodegeneration.