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

Neurobiol Dis. 2019 Jan;121:263-273. doi: 10.1016/j.nbd.2018.10.014. Epub 2018 Oct 19.


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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3 / genetics
  • Ataxin-3 / metabolism*
  • Dendrites / pathology
  • Humans
  • Machado-Joseph Disease / metabolism*
  • Machado-Joseph Disease / pathology
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism*
  • Peptides / genetics
  • Protein Aggregation, Pathological / metabolism
  • Purkinje Cells / metabolism*
  • Purkinje Cells / pathology
  • Receptors, Metabotropic Glutamate / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction


  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Peptides
  • Receptors, Metabotropic Glutamate
  • Repressor Proteins
  • Rora protein, mouse
  • metabotropic glutamate receptor type 1
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3