title: Spinocerebellar ataxia type 12: clues to pathogenesis.
abstract: Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disease characterized by tremor, gait abnormalities, and neuropsychiatric syndromes. The location of the causative CAG/CTG expansion mutation in PPP2R2B, a gene encoding regulatory units of the protein phosphatase 2A, may provide unique insights into the pathogenesis of neurodegeneration.
  
  
  
  The first neuropathological examination of a brain from an SCA12 patient revealed both cerebellar and cerebral cortical atrophy, with a noted loss of Purkinje cells and no evidence of polyglutamine aggregates. Molecular investigations have demonstrated considerable complexity of PPP2R2B, which appears to encode at least eight isoforms each with a different N-terminal region. The repeat potentially influences PPP2R2B expression, and is itself included in several splice variants, falling within an open reading frame of at least one of these variants.
  
  
  
  The current data suggest at least two nonmutually exclusive hypotheses of SCA12 neurodegeneration. First, the repeat may influence PPP2R2B expression, by altering promoter activity, splicing, or transcript stability. This hypothesis would predict that the mutation changes the regulation of protein phosphatase 2A, with implications for the phosphoproteome. Alternatively, the repeat itself may be expressed and have toxic properties, though perhaps not through polyglutamine tracts. Either hypothesis may provide novel insight into the pathogenesis of neurodegeneration.
authors.affiliation: aDepartment of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine bDepartment of Neurology cProgram of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Cohen
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
mesh_terms: D001921:Brain / Q000473:pathology*; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D054648:Protein Phosphatase 2 / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000209:etiology* / Q000235:genetics / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C505936:PPP2R2B protein, human; D054648:Protein Phosphatase 2