Zhang Yunong, Snider Adam, Willard Lloyd, Takemoto Dolores J, Lin Dingbo
Department of Human Nutrition, Kansas State University, 212 Justin Hall, Manhattan, KS 66506, USA.
Biochem Biophys Res Commun. 2009 Jan 16;378(3):524-8. doi: 10.1016/j.bbrc.2008.11.082. Epub 2008 Dec 3.
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.
14型脊髓小脑共济失调（SCA14）是一种由PKCγ基因突变引起的常染色体显性神经退行性疾病。本研究的目的是确定PKCγ H101Y SCA14突变对转基因小鼠浦肯野细胞的影响。结果表明，在4周龄的PKCγ H101Y SCA14转基因小鼠中，观察到HA标签的PKCγ H101Y突变蛋白的野生型PKCγ样浦肯野细胞定位、形态改变和浦肯野细胞丢失。还观察到转基因小鼠后肢典型的紧握反应失败。此外，PKCγ H101Y SCA14突变导致PKCγ H101Y SCA14转基因小鼠缺乏总细胞PKCγ酶活性、丝氨酸连接蛋白57磷酸化缺失以及半胱天冬酶-12激活。结果清楚地表明，为维持浦肯野细胞，需要PKCγ控制间隙连接。据我们所知，这是第一只模拟人类SCA14突变的转基因小鼠。
