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 RIS Download
Animals | Ataxin-1 | Ataxins | 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