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.
Subject(s)
Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/metabolism , Nuclear Proteins/deficiency , Nuclear Proteins/metabolism , Purkinje Cells/cytology , Receptors, Cytoplasmic and Nuclear/metabolism , Trans-Activators/metabolism , 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/genetics , Nuclear Proteins/genetics , Nuclear Receptor Subfamily 1, Group F, Member 1 , Protein Binding , Protein Interaction Mapping , Purkinje Cells/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Cytoplasmic and Nuclear/deficiency , Trans-Activators/deficiencyABSTRACT
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the disease protein, ataxin 1. To elucidate cellular pathways involved in SCA1, we used DNA microarrays to determine the pattern of gene expression in SCA1 transgenic mice at two specific times in the disease process; 5 weeks, a timepoint prior to onset of pathology, and 12 weeks, at the midpoint of the disease progression. Taking advantage of the availability of three SCA1 transgenic mouse lines, each expressing a different form of ataxin-1, we utilized a strategy that resulted in the identification of a limited number of genes with an altered pattern of expression specific to the development of disease. By comparing the pattern of gene expression in the SCA1 ataxic B05-ataxin-1[82Q] transgenic mouse line with those seen in two non-ataxic lines, A02-ataxin-1[30Q] and K772T-[82Q], nine genes were identified whose expression was consistently altered in the cerebellum of B05[82Q] mice at 5 and 12 weeks of age. Interestingly, five of the genes in this group form a biological cohort centered on glutamate signaling pathways in Purkinje cells.
