Molecular Pathogenesis of Spinocerebellar Ataxia Type 6

Abstract

Summary: Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by abnormal expansions of a trinucleotide CAG repeat in exon 47 of the CACNA1A gene, which encodes the ␣1A subunit of the P/Q-type voltage-gated calcium channel. The CAG repeat expansion is translated into an elongated polyglutamine tract in the carboxyl terminus of the ␣1A subunit. The ␣1A subunit is the main pore-forming subunit of the P/Q-type calcium channel. Patients with SCA6 suffer from a severe form of progressive ataxia and cerebellar dysfunction. Design of treatments for this disorder will depend on better definition of the mechanism of disease. As a disease arising from a mutation in an ion channel gene, SCA6 may behave as an ion channelopathy, and may respond to attempts to modulate or correct ion channel function. Alternatively, as a disease in which the mutant protein contains an expanded polyglutamine tract, SCA6 may respond to the targets of drug therapies developed for Huntington's disease and other polyglutamine disorders. In this review we will compare SCA6 to other polyglutamine diseases and channelopathies, and we will highlight recent advances in our understanding of ␣1A subunits and SCA6 pathology. We also propose a mechanism for how two seemingly divergent hypotheses can be combined into a cohesive model for disease progression.

The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases: Table 1.

“…For example, in SCA6, the small polyQ expansions seen in the affected protein, the alpha subunit of the P/Qvoltage gated calcium channel, affect channel function (Kordasiewicz and Gomez 2007). The relative contribution of impaired channel function and polyQ toxicity to SCA6 pathology is still the subject of some debate (Kordasiewicz and Gomez 2007).…”

“…For example, in SCA6, the small polyQ expansions seen in the affected protein, the alpha subunit of the P/Qvoltage gated calcium channel, affect channel function (Kordasiewicz and Gomez 2007). The relative contribution of impaired channel function and polyQ toxicity to SCA6 pathology is still the subject of some debate (Kordasiewicz and Gomez 2007). Small increases in the number of glutamines are also associated with a reduced transactivation ability of the androgen receptor (Mhatre et al 1993;Chamberlain et al 1994).…”

Familial Hemiplegic Migraine

“…In humans, mutations in the CACNA1A gene cause, in addition to FHM1, a few autosomal dominant neurological disorders characterized by cerebellar dysfunction, such as episodic ataxia type 2 (that may be associated with absence epilepsy in a few cases) and spinocerebellar ataxia type 6 9,26,27 (compare, Strupp 28 and Gomez 29 31,35,37,38 Recently, the generation of knockin mice carrying two different FHM1 mutations (R192Q and S218L) allowed the first analysis of mutant channels expressed at their endogenous level in neurons. [39][40][41] The studies in heterologous expression systems showed that the FHM1 mutations alter many biophysical properties of human Ca V 2.1 channels, in a complex way.…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…Onset generally occurs in the fifth decade of life and lifespan is not shortened [108,109]. Neurodegeneration occurs selectively in the PCs of the cerebellum with no neuropathy in other neurons, making it a pure cerebellar ataxia [110]. Unlike other polyQ diseases, only certain isoforms of Ca v 2.1 contain the expanded glutamine tract [111,112].…”