ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism.
ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism.
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DOI：
10.1016/j.neuron.2018.02.013
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发表时间：
2018-03-21
期刊：
影响因子：
16.2
通讯作者：
Orr HT
中科院分区：
文献类型：
--
作者：
Rousseaux MWC;Tschumperlin T;Lu HC;Lackey EP;Bondar VV;Wan YW;Tan Q;Adamski CJ;Friedrich J;Twaroski K;Chen W;Tolar J;Henzler C;Sharma A;Bajić A;Lin T;Duvick L;Liu Z;Sillitoe RV;Zoghbi HY;Orr HT
多聚谷氨酰胺(PolyQ)疾病是由不同基因中翻译的CAG重复序列扩大导致蛋白质功能改变引起的。在脊髓小脑型共济失调1型(SCA1)中，多聚Q扩张型ataxin-1(ATXN1)功能增强与小脑病理有关。小脑毒性在多大程度上依赖于其同源伙伴Capicua(CIC)，而不是其他相互作用者，目前尚不清楚。目前也没有确定小脑中ATXN1-CIC复合体的缺失是否与疾病的发病机制有关。在本研究中，我们在体内独家阻断了ATXN1-CIC的相互作用，并表明它是SCA1小脑毒性的症结所在。重要的是，小脑中CIC的丢失不会导致共济失调或浦肯野细胞变性。这些功能获得和功能丧失模型的表达谱，再加上来自SCA1患者的IPSC衍生神经元的数据，支持ATXN1-CIC复合体功能获得是毒性的主要驱动因素的机制。Rousseaux、Tschumperlin、Lu及其同事表明，ATXN1-CIC复合体的形成对于多聚Q扩展的ATXN1介导的毒性至关重要。他们发现，这种复合体通过SCA1小鼠和SCA1患者来源的神经元的小脑功能获得机制来调节其效果。
Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity. Rousseaux, Tschumperlin, Lu, and colleagues show that formation of the ATXN1-CIC complex is critical for polyQ-expanded ATXN1-mediated toxicity. They find that this complex mediates its effects through a gain-of-function mechanism in the cerebellum of SCA1 mice and SCA1 patient-derived neurons.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
10.5
作者：
Kim, Eunji;Lu, Hsiang-Chih;Song, Ji-Joon
通讯作者：
Song, Ji-Joon
影响因子：
16.2
作者：
Ingram M;Wozniak EAL;Duvick L;Yang R;Bergmann P;Carson R;O'Callaghan B;Zoghbi HY;Henzler C;Orr HT
通讯作者：
Orr HT
影响因子：
16.2
作者：
Katsuno, M;Adachi, H;Sobue, G
通讯作者：
Sobue, G
DOI：
10.1126/science.1212673
发表时间：
2011-11-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fryer JD;Yu P;Kang H;Mandel-Brehm C;Carter AN;Crespo-Barreto J;Gao Y;Flora A;Shaw C;Orr HT;Zoghbi HY
通讯作者：
Zoghbi HY