4.7 Article

Pharmacological enhancement of retinoid-related orphan receptor a function mitigates spinocerebellar ataxia type 3 pathology

Journal

NEUROBIOLOGY OF DISEASE
Volume 121, Issue -, Pages 263-273

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2018.10.014

Keywords

Cerebellum; Purkinje cell; Spinocerebellar ataxia type 3; Machado Joseph disease; AAV vector; Retinoid-related orphan receptor alpha; Type 1 metabotropic glutamate receptor; Slow excitatory postsynaptic current

Categories

Funding

  1. JSPS KAKENHI [15H04254, 18H02521, 15K18330, 17K14929]
  2. program for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS), Japan Agency for Medical Research and Development (AMED)
  3. Research on Measures for Intractable Diseases (Ataxic Diseases and Neurodegenerative Diseases), Ministry of Health, Labor and Welfare
  4. Gunma University Initiative for Advanced Research (GIAR)
  5. Grants-in-Aid for Scientific Research [18H02521, 17K14929, 15K18330, 15H04254] Funding Source: KAKEN

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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 a (ROR alpha), 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 ROR alpha/gamma agonist. These results suggest that ROR alpha plays a key role in mutant ATXN3-mediated aberrant phenotypes and that the pharmacological enhancement of ROR alpha could function as a method for therapeutic intervention in SCA3.

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