Loss of Purkinje cells in the PKCgamma H101Y transgenic mouse.
Spinocerebellar ataxia type 14 (SCA14) is an autosomal, dominant neurodegenerative disorder caused by mutations in PKCgamma. The objective of this study was to determine effects of PKCgamma H101Y SCA14 mutation on Purkinje cells in the transgenic mouse. Results demonstrated that wild type PKCgamma-like Purkinje cell localization of HA-tagged PKCgamma H101Y mutant proteins, altered morphology and loss of Purkinje cells were observed in the PKCgamma H101Y SCA14 transgenic mouse at four weeks of age. Failure of stereotypical clasping responses in the hind limbs of transgenic mice was also observed. Further, PKCgamma H101Y SCA14 mutation caused lack of total cellular PKCgamma enzyme activity, loss of connexin 57 phosphorylation on serines, and activation of caspase-12 in the PKCgamma H101Y SCA14 transgenic mouse. Results clearly demonstrate a need for PKCgamma control of gap junctions for maintenance of Purkinje cells. This is the first transgenic mouse to our knowledge which models a human SCA14 mutation.
Zhang
Yunong
Y
Department of Human Nutrition, Kansas State University, 212 Justin Hall, Manhattan, KS 66506, USA.
Snider
Adam
A
Willard
Lloyd
L
Takemoto
Dolores J
DJ
Lin
Dingbo
D
D019943:Amino Acid Substitution; D000818:Animals; D053454:Caspase 12 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006639:Histidine / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics*; D011689:Purkinje Cells / Q000201:enzymology / Q000473:pathology*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology*; D014443:Tyrosine / Q000235:genetics
D017630:Connexins; C119811:Gja10 protein, mouse; D014443:Tyrosine; D006639:Histidine; C087857:protein kinase C gamma; D011493:Protein Kinase C; D053454:Caspase 12