Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia

Ravi Chopra, Aaron H. Wasserman, Stefan M. Pulst, Chris I. De Zeeuw, Vikram G. Shakkottai

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Among the many types of neurons expressing protein kinase C (PKC) enzymes, cerebellar Purkinje neurons are particularly reliant on appropriate PKC activity for maintaining homeostasis. The importance of PKC enzymes in Purkinje neuron health is apparent as mutations in PRKCG (encoding PKCγ) cause cerebellar ataxia. PRKCG has also been identified as an important node in ataxia gene networks more broadly, but the functional role of PKC in other forms of ataxia remains unexplored, and the mechanisms by which PKC isozymes regulate Purkinje neuron health are not well understood. Here, we investigated how PKC activity influences neurodegeneration in inherited ataxia. Using mouse models of spinocerebellar ataxia type 1 (SCA1) and 2 (SCA2) we identify an increase in PKC-mediated substrate phosphorylation in two different forms of inherited cerebellar ataxia. Normalizing PKC substrate phosphorylation in SCA1 and SCA2 mice accelerates degeneration, suggesting that the increased activity observed in these models is neuroprotective. We also find that increased phosphorylation of PKC targets limits Purkinje neuron membrane excitability, suggesting that PKC activity may support Purkinje neuron health by moderating excitability. These data suggest a functional role for PKC enzymes in ataxia gene networks, and demonstrate that increased PKC activity is a protective modifier of degeneration in inherited cerebellar ataxia.

Original languageEnglish (US)
Pages (from-to)1396-1410
Number of pages15
JournalHuman molecular genetics
Issue number8
StatePublished - Apr 15 2018
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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