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RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.

Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited, typically adult onset, polyglutamine neurodegenerative diseases. To examine whether development impacts SCA1, we used a conditional transgenic mouse model of SCA1 to delay the postnatal expression of mutant ATXN1 until after completion of cerebellar development. Delayed postnatal expression of mutant ATXN1 led to a substantial reduction in severity of disease in adults in comparison with early postnatal gene expression. This was linked to a destabilization of RORalpha, a transcription factor critical for cerebellar development. In SCA1 mice, there was a depletion of RORalpha and a reduction in expression of genes controlled by RORalpha. Partial loss of RORalpha enhanced mutant ATXN1 pathogenicity. Additionally, evidence points to the existence of a complex containing ATXN1, RORalpha, and the RORalpha coactivator Tip60. These studies indicate RORalpha and Tip60 have a role in SCA1 and suggest a mechanism by which compromising cerebellar development contributes to severity of neurodegeneration in an adult.

Pubmed ID: 17110330


  • Serra HG
  • Duvick L
  • Zu T
  • Carlson K
  • Stevens S
  • Jorgensen N
  • Lysholm A
  • Burright E
  • Zoghbi HY
  • Clark HB
  • Andresen JM
  • Orr HT



Publication Data

November 17, 2006

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS22920
  • Agency: NINDS NIH HHS, Id: NS27699
  • Agency: NINDS NIH HHS, Id: NS45667

Mesh Terms

  • Animals
  • COS Cells
  • Cercopithecus aethiops
  • Disease Progression
  • Down-Regulation
  • Histone Acetyltransferases
  • Humans
  • Mice
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Mutant Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Protein Binding
  • Protein Interaction Mapping
  • Purkinje Cells
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Trans-Activators