Tuesday, May 13, 2025
5/13/2025
Molecular Pathogenesis of spinocerebellar ataxia type 12 - PROJECT SUMMARY Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant neurodegenerative disease, discovered and characterized by our group, notable clinically for tremor, gait abnormalities, and neuropsychiatric syndromes, and neuropathologically for atrophy in cerebral cortex and cerebellum. SCA12 is caused by a CAG/CTG expansion mutation in PPP2R2B, a gene encoding brain-specific regulatory units of protein phosphatase 2A (PP2A). Normal alleles carry 4 to 31 triplets, whereas disease alleles carry 43 to 78 triplets. SCA12 is the second most common ataxia in North India, with cases of SCA12 detected in the United States, Italy, and China. There is no treatment. Our preliminary data indicates that PPP2R2B contains at least 16 exons with multiple alternative splice variants, resulting in at least 8 protein isoforms (termed B1-B8) with different N terminal domains, among which Bβ1 and Bβ2 are by far the most abundant and best characterized. The N-terminal domains contribute to the localization of the PP2A holoenzyme, and hence their relative abundance may be critical in establishing patterns of protein phosphorylation. The repeat is located in the 5’ region of exon 7 in a predicted promoter region, but is also contained within the transcripts of alternative splice variants. Based on extensive preliminary data, we hypothesize that the CAG repeat expansion in SCA12 alters PPP2R2B expression and splicing, leading to changes in PP2A targeting that contribute to SCA12 pathogenesis by alteration of phosphoproteome. Secondarily, we hypothesize that missplicing induced by repeat expansion generates a transcript encoding a toxic polyserine tract that contributes to SCA12 pathogenesis. Our aims are each designed to explore a specific aspect of SCA12 pathogenesis, and simultaneously to explore more general principles of neurodegeneration related to repeat expansion and the function of PP2A, using genetically engineered mice and human iPSCs. In Aim 1, we will determine the effect of the SCA12 mutation on PPP2R2B expression. In Aim 2, we will determine the effect of abnormal PPP2R2B expression on PP2A substrate targeting and the phosphoproteome. In Aim 3, we will determine how changes in PP2A substrate targets and aberrantly expressed polyserine contribute to neurotoxicity. If our hypothesis is correct, SCA12 pathogenesis derives from repeat-expansion-induced changes in PPP2R2B expression that 1) alters PP2A substrates targets and hence the phosphoproteome, and 2) generates toxic polyserine tracts. Establishing these pathways will establish multiple potential targets for therapeutic intervention in SCA12. At the same time, our experiments will more generally establish the potential effect of repeat expansion on promoter and splicing function, and the role of PP2A dysregulation in neurodegeneration, of particular interest given evidence of PP2A dysregulation in other neurodegenerative disorders, such as Alzheimer’s disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).