Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6.
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Ca(v)2.1 voltage-gated calcium channel. To elucidate how the expanded polyglutamine tract in this plasma membrane protein causes the disease, we created a unique knockin mouse model that modestly overexpressed the mutant transcripts under the control of an endogenous promoter (MPI-118Q). MPI-118Q mice faithfully recapitulated many features of SCA6, including selective Purkinje cell degeneration. Surprisingly, analysis of inclusion formation in the mutant Purkinje cells indicated the lysosomal localization of accumulated mutant Ca(v)2.1 channels in the absence of autophagic response. The lack of cathepsin B, a major lysosomal cysteine proteinase, exacerbated the loss of Purkinje cells and was accompanied by an acceleration of inclusion formation in this model. Thus, the pathogenic mechanism of SCA6 involves the endolysosomal degradation pathway, and unique pathological features of this model further illustrate the pivotal role of protein context in the pathogenesis of polyglutamine diseases.
The Center for Brain Integration Research and Department of Neurology and Neurological Science,  Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8519,  Japan.
Toshinori
T
Unno
Minoru
M
Wakamori
Masato
M
Koike
Yasuo
Y
Uchiyama
Kinya
K
Ishikawa
Hisahiko
H
Kubota
Takashi
T
Yoshida
Hiroko
H
Sasakawa
Christoph
C
Peters
Hidehiro
H
Mizusawa
Kei
K
Watase
D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D008247:Lysosomes / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011689:Purkinje Cells / Q000473:pathology*; D020754:Spinocerebellar Ataxias / Q000473:pathology*