Global Knockdown of Retinoid-related Orphan Receptor a in Mature Purkinje Cells Reveals Aberrant Cerebellar Phenotypes of Spinocerebellar Ataxia

orphan receptor a (RORa) is a transcription factor expressed in a variety of tissues throughout the body. Knockout of RORa 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 RORa 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 RORa reduction in PCs is involved in the disease pathology. Here, RORa expression was downregulated specifically in mature mouse PCs by intravenous infusion of blood?brain barrier-permeable adeno-associated virus (AAV), expressing a microRNA against RORa (miR-RORa) under the control of the PC-specific L7-6 promoter. The systemic AAV infusion led to extensive transduction of PCs. The RORa knock-down caused degeneration of PCs including disruption of the PC monolayer alignment and dendrite atrophy. In behavioral experiments, mice expressing miRRORa showed motor learning deficits, and later, overt cerebellar ataxia. Thus, RORa in mature PCs plays pivotal roles in maintenance of PC dendrites and the monolayer alignment, and consequently, motor learning and motor function. Decrease in RORa expression in PCs could be a primary etiology of the cerebellar symptoms in patients with SCA1 and SCA3/MJD. This article is part of a Special Issue entitled: In Memoriam: Masao Ito?A Visionary Neuroscientist with a Passion for the Cerebellum. ? 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

Loss of orphan receptor a (RORa) leads to various impairments in the body, including defects in cerebellar development, circadian rhythm, lipid metabolism, immune function, and bone development. Studies have shown significant reduction of RORa expression in Purkinje cells of certain mouse models, but the extent of this reduction's involvement in disease pathology remains unclear.