Journal
NEUROBIOLOGY OF DISEASE
Volume 121, Issue -, Pages 263-273Publisher
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
- JSPS KAKENHI [15H04254, 18H02521, 15K18330, 17K14929]
- program for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS), Japan Agency for Medical Research and Development (AMED)
- Research on Measures for Intractable Diseases (Ataxic Diseases and Neurodegenerative Diseases), Ministry of Health, Labor and Welfare
- Gunma University Initiative for Advanced Research (GIAR)
- 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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