Proteolytic cleavage and cellular toxicity of the human alpha1A calcium channel in spinocerebellar ataxia type 6.
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by small CAG repeat expansion in the alpha1A calcium channel gene. We found that the human alpha1A 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 alpha1A calcium channel, regardless of polyglutamine tract length. In cells stably transfected with plasmids of full-length alpha1A 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.
Kubodera
Takayuki
T
Department of Neurology and Neurological Science, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Yokota
Takanori
T
Ohwada
Kiyoshi
K
Ishikawa
Kinya
K
Miura
Hiroyuki
H
Matsuoka
Takeshi
T
Mizusawa
Hidehiro
H
D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D019680:Trinucleotide Repeat Expansion / Q000502:physiology; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; D018076:DNA, Complementary; D012333:RNA, Messenger; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type