Global Knockdown of Retinoid-related Orphan Receptor α in Mature Purkinje Cells Reveals Aberrant Cerebellar Phenotypes of Spinocerebellar Ataxia
Global Knockdown of Retinoid-related Orphan Receptor α in Mature Purkinje Cells Reveals Aberrant Cerebellar Phenotypes of Spinocerebellar Ataxia
复制标题
成熟浦肯野细胞中类维生素A相关孤儿受体α的整体敲低揭示了脊髓小脑共济失调的异常小脑表型
DOI：
10.1016/j.neuroscience.2020.04.004
复制
发表时间：
2020
期刊：
影响因子：
3.3
通讯作者：
Hirai Hirokazu
中科院分区：
文献类型：
--
作者：
Yasui Hiroyuki;Matsuzaki Yasunori;Konno Ayumu;Hirai Hirokazu
维甲酸相关孤儿受体α（RORα）是一种在全身多种组织中表达的转录因子。RORα基因敲除可导致多种损伤，包括小脑发育、昼夜节律、脂质代谢、免疫功能和骨发育的缺陷。先前的研究表明，脊髓小脑共济失调（SCA）1型和3型/MJD（Machado-Joseph病）模型小鼠的浦肯野细胞（PC）中RORα表达显著降低。然而，目前尚不清楚PC中RORα降低在疾病病理学中的程度。在此，通过静脉输注血脑屏障可穿透的腺相关病毒（AAV），在PC特异性L7-6启动子的控制下表达针对RORα的microRNA（miR-RORα），在成熟小鼠PC中特异性下调RORα表达。全身性AAV输注导致PC的广泛转导。RORα敲低导致PC变性，包括PC单层排列的破坏和树突萎缩。在行为实验中，表达miR-RORα的小鼠表现出运动学习缺陷，随后出现明显的小脑共济失调。因此，成熟PC中的RORα在PC树突和单层排列的维持中起着关键作用，因此，运动学习和运动功能。PC中RORα表达降低可能是SCA 1和SCA 3/MJD患者小脑症状的主要病因。
Retinoid-related orphan receptor α (RORα) is a transcription factor expressed in a variety of tissues throughout the body. Knockout of RORα leads to various impairments, including defects in cerebellar development, circadian rhythm, lipid metabolism, immune function, and bone development. Previous studies have shown significant reduction of RORα expression in Purkinje cells (PCs) of spinocerebellar ataxia (SCA) type 1 and type 3/MJD (Machado–Joseph disease) model mice. However, it remains unclear to what extent the RORα reduction in PCs is involved in the disease pathology. Here, RORα expression was downregulated specifically in mature mouse PCs by intravenous infusion of blood–brain barrier-permeable adeno-associated virus (AAV), expressing a microRNA against RORα (miR-RORα) under the control of the PC-specific L7-6 promoter. The systemic AAV infusion led to extensive transduction of PCs. The RORα knock-down caused degeneration of PCs including disruption of the PC monolayer alignment and dendrite atrophy. In behavioral experiments, mice expressing miR-RORα showed motor learning deficits, and later, overt cerebellar ataxia. Thus, RORα in mature PCs plays pivotal roles in maintenance of PC dendrites and the monolayer alignment, and consequently, motor learning and motor function. Decrease in RORα expression in PCs could be a primary etiology of the cerebellar symptoms in patients with SCA1 and SCA3/MJD.