Pharmacological enhancement of retinoid-related orphan receptor α function mitigates spinocerebellar ataxia type 3 pathology
Pharmacological enhancement of retinoid-related orphan receptor α function mitigates spinocerebellar ataxia type 3 pathology
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DOI：
10.1016/j.nbd.2018.10.014
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发表时间：
2019-01
影响因子：
6.1
通讯作者：
Masashi Watanave;Chiaki Hoshino;Ayumu Konno;Y. Fukuzaki;Y. Matsuzaki;Tohru Ishitani;H. Hirai
中科院分区：
文献类型：
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作者：
Masashi Watanave;Chiaki Hoshino;Ayumu Konno;Y. Fukuzaki;Y. Matsuzaki;Tohru Ishitani;H. Hirai
小脑浦肯野细胞(PC)是小脑皮质的唯一输出神经元，其损伤会导致运动障碍。脊髓小脑型共济失调3型(SCA3，又称Machado-Joseph病)是一种遗传性神经退行性疾病，由致病蛋白ATXN3中的多谷氨酰胺束异常扩张引起。SCA3影响中枢神经系统的多种细胞，包括小脑中的细胞。为了揭示SCA3的病理机制，我们使用腺相关病毒血清9型(AAV9)载体在成熟野生型小鼠的小脑神经元中表达全长ATXN3和异常扩张的89多聚谷氨酰胺拉伸(ATXN3[Q89])。表达ATXN3[Q89]的小鼠表现出运动障碍，其程度取决于病毒滴度。小脑免疫组织化学显示PC核聚集体泛素化；PC树突变性；多种蛋白质显著减少，包括转录因子维甲酸相关孤儿受体α(RoRα)和1型代谢性谷氨酸受体(MGluR1)信号分子。对表达ATXN3[Q89]的PC进行膜片钳分析，发现mGluR1信号明显缺陷。值得注意的是，一次注射RoRα/γ激动剂SR1078可以抑制行为、形态和功能缺陷的出现。这些结果表明，RoRα在突变型α介导的突变表型中起关键作用，其药理作用增强可作为治疗SCA3的一种手段。
Cerebellar Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex, and damage to PCs results in motor deficits. Spinocerebellar ataxia type 3 (SCA3, also known as Machado–Joseph disease), a hereditary neurodegenerative disease, is caused by an abnormal expansion of the polyglutamine tract in the causative ATXN3 protein. SCA3 affects a wide range of cells in the central nervous system, including those in the cerebellum. To unravel SCA3 pathology, we used adeno-associated virus serotype 9 (AAV9) vectors to express full-length ATXN3 with an abnormally expanded 89 polyglutamine stretch (ATXN3[Q89]) in cerebellar neurons of mature wild-type mice. Mice expressing ATXN3[Q89] exhibited motor impairment in a manner dependent on the viral titer. Immunohistochemistry of the cerebellum showed ubiquitinated nuclear aggregates in PCs; degeneration of PC dendrites; and a significant decrease in multiple proteins including retinoid-related orphan receptor α (RORα), a transcription factor, and type 1 metabotropic glutamate receptor (mGluR1) signaling molecules. Patch clamp analysis of ATXN3[Q89]-expressing PCs revealed marked defects in mGluR1 signaling. Notably, the emergence of behavioral, morphological, and functional defects was inhibited by a single injection of SR1078, an RORα/γ agonist. These results suggest that RORα plays a key role in mutant ATXN3-mediated aberrant phenotypes and that the pharmacological enhancement of RORα could function as a method for therapeutic intervention in SCA3.