Spinocerebellar ataxia type 12: clues to pathogenesis

Rachael L. Cohen, Russell Louis Margolis

Research output: Contribution to journalArticle

Abstract

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Original languageEnglish (US)
JournalCurrent Opinion in Neurology
DOIs
StateAccepted/In press - Sep 29 2016

Fingerprint

Protein Phosphatase 2
Mutation
Poisons
Purkinje Cells
Tremor
Regulator Genes
Gait
Neurodegenerative Diseases
Open Reading Frames
Atrophy
Protein Isoforms
Brain
Spinocerebellar Ataxia 12
polyglutamine

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Spinocerebellar ataxia type 12 : clues to pathogenesis. / Cohen, Rachael L.; Margolis, Russell Louis.

In: Current Opinion in Neurology, 29.09.2016.

Research output: Contribution to journalArticle

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