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

Cell. 2006 Nov 17;127(4):697-708. doi: 10.1016/j.cell.2006.09.036.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Ataxin-1
  • Ataxins
  • COS Cells
  • Chlorocebus aethiops
  • Disease Progression
  • Down-Regulation / genetics
  • Histone Acetyltransferases / metabolism
  • Humans
  • Mice
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Mutant Proteins / metabolism
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / deficiency*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Protein Binding
  • Protein Interaction Mapping
  • Purkinje Cells / cytology*
  • Purkinje Cells / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Trans-Activators / deficiency
  • Trans-Activators / metabolism*

Substances

  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Atxn1 protein, mouse
  • Mutant Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • RNA, Messenger
  • RORA protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Trans-Activators
  • Histone Acetyltransferases