Moseley Melinda L, Zu Tao, Ikeda Yoshio, Gao Wangcai, Mosemiller Anne K, Daughters Randy S, Chen Gang, Weatherspoon Marcy R, Clark H Brent, Ebner Timothy J, Day John W, Ranum Laura P W
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Nat Genet. 2006 Jul;38(7):758-69. doi: 10.1038/ng1827. Epub 2006 Jun 25.
We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance. We now report a transgenic mouse model in which the full-length human SCA8 mutation is transcribed using its endogenous promoter. (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurological phenotype with in vivo imaging showing reduced cerebellar-cortical inhibition. 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript (ataxin 8, ATXN8) spanning the repeat in the CAG direction. The neurological phenotype in SCA8 BAC expansion but not BAC control lines demonstrates the pathogenicity of the (CTG-CAG)n expansion. Moreover, the expression of noncoding (CUG)n expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggests SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and RNA levels.
我们之前报道过，(CTG)n 扩增会导致 8 型脊髓小脑共济失调（SCA8），这是一种具有降低外显率的缓慢进行性共济失调。我们现在报道一种转基因小鼠模型，其中全长人类 SCA8 突变通过其内源启动子进行转录。(CTG)116 扩增而非 (CTG)11 对照品系会出现进行性神经表型，体内成像显示小脑皮质抑制减弱。SCA8 扩增小鼠和人类 SCA8 尸检组织中小脑浦肯野细胞和脑干神经元中的 1C2 阳性核内包涵体是由一种多聚谷氨酰胺蛋白的翻译产生的，该蛋白由一个先前未鉴定的反向转录本（共济失调蛋白 8，ATXN8）编码，该转录本在 CAG 方向跨越重复序列。SCA8 BAC 扩增品系而非 BAC 对照品系中的神经表型证明了(CTG-CAG)n 扩增的致病性。此外，非编码(CUG)n 扩增转录本（共济失调蛋白 8 反义链，ATXN8OS）的表达以及核内多聚谷氨酰胺包涵体的发现表明，SCA8 的发病机制涉及蛋白质和 RNA 水平的毒性功能获得机制。
