|Education||DVM, University of Missouri|
Spinocerebellar ataxia type 12 (SCA12) is a rare form of human autosomal dominant progressive neurodegenerative disease. SCA12 is caused by a CAG trinucleotide expansion mutation (normal <28 triplets, disease 46-78) in a promoter region of PPP2R2B, which encodes a regulatory subunit of the ubiquitous serine/threonine phosphatase, PP2A. PP2A is a trimer enzyme composed of a A structural, B regulatory, and C catalytic subgroups. There are seven known isoforms of PPP2R2B, named Bβ1 to Bβ7. The most abundant transcript is Bβ1. Clinically the disease is characterized by midlife-onset of movement abnormalities, with prominent tremor and gait disturbance, and less consistently psychiatric and cognitive disturbances. Pathologic findings include generalized atrophy of the cerebral cortex and cerebellum, with prominent loss of Purkinje cells. Currently there are no known drugs or treatments that can slow or stop the progression of SCA12 or any CAG trinucleotide expansion disease, such as Huntington’s Disease (HD). While the pathogenesis of SCA12 remains to be elucidated, our preliminary findings suggest that the trinucleotide expansion mutation functions to increase the activity of the PPP2R2B promoter. We hypothesize that the trinucleotide expansion mutation in SCA12 increases expression of the Bβ1 transcript and protein, which subsequently displace other PP2A regulatory subunits, leading to a shift of PP2A phosphatase substrates, resulting in alterations of the phosphoproteome and eventually neurotoxicity.
O’Hearn E, et al. Neuropathology and cellular pathogenesis of spinocerebellar ataxia type 12. Movement Disorders; Mov Disord. 2015 Sep 4. doi: 10.1002/mds.26348. PMID:26340331
Sun X1, Li PP2, Zhu S2, Cohen R2, Marque LO2, Ross CA3, Pulst SM4, Chan HY5, Margolis RL6, Rudnicki DD7. Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65. Sci. Rep. 5, 12521; doi: 10.1038/srep12521 PMID:26218986.