Proteolytic cleavage and cellular toxicity of the human α1A calcium channel in spinocerebellar ataxia type 6
Review articleOpen access
Abstract:

AbstractSpinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by small CAG repeat expansion in the α1A calcium channel gene. We found that the human α1A calcium channel protein expressed in human embryonic kidney 293T cells produces a 75 kDa C-terminal fragment. This fragment is more toxic to cells than the full-length α1A calcium channel, regardless of polyglutamine tract length. In cells stably transfected with plasmids of full-length α1A calcium channel cDNAs, the C-terminal fragment protein is present in the mutant transformant but not in the wild-type one, indicative that this C-terminal fragment with the expanded polyglutamine tract is more resistant to proteolysis than that with the normal sized polyglutamine tract. We speculate that the toxic C-terminal fragment, in which resistance to proteolysis is rendered by the expanded polyglutamine, has a key role in the pathological mechanism of SCA6.

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