Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17
Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17
复制标题
小脑富集蛋白 INPP5A 有助于 17 型脊髓小脑共济失调小鼠模型的选择性神经病理学
DOI：
10.1038/s41467-020-14931-8
复制
发表时间：
2020-02-27
影响因子：
16.6
通讯作者：
Li, Shihua
中科院分区：
文献类型：
--
作者：
Liu, Qiong;Huang, Shanshan;Li, Shihua
脊髓小脑性共济失调17(SCA17)是由TATA盒结合蛋白(TBP)中的多聚谷氨酰胺(PolyQ)膨胀引起的。SCA17小脑的选择性神经变性提出了一个问题，即为什么在不同的多Q疾病中，普遍表达的多聚Q蛋白可以导致不同大脑区域的神经退化。通过对腺相关病毒的立体定位注射，在成年野生型小鼠不同脑区表达突变型TBP，我们发现成年小脑神经元对突变型TBP特别敏感。在SCA17基因敲除小鼠中，突变的TBP抑制SP1介导的基因转录，下调INPP5A，一种在小脑中高度丰富的蛋白质。CRISPR/Cas9介导的野生型小鼠小脑中Inpp5的缺失导致了浦肯野细胞的变性，而在SCA17敲入小鼠中，Inpp5的过表达降低了三磷酸肌醇(IP3)的水平，改善了浦肯野细胞的变性。我们的发现证明了一种组织特异性蛋白在多聚Q蛋白介导的选择性神经病理学中的重要贡献。
Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutantTBPin different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion ofInpp5ain the cerebellum of wild-type mice leads to Purkinje cell degeneration, andInpp5aoverexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology.