Activation of mutant protein kinase Cγ leads to aberrant sequestration and impairment of its cellular function

Mutations in protein kinase C gamma (PKC gamma) cause the neurodegenerative disease spinocerebellar ataxia type 14 (SCA14). In this study, expression of an extensive panel of known SCA14-associated PKC gamma mutations as fusion proteins in cell culture led to the consistent formation of cytoplasmic aggregates in response to purinoceptor stimulation. Aggregates co-stained with antibodies to phosphorylated PKC gamma and the early endosome marker EEA1 but failed to redistribute to the cell membrane under conditions of oxidative stress. These studies suggest that Purkinje cell damage in SCA14 may result from a reduction of PKC gamma activity due its aberrant sequestration in the early endosome compartment. (C) 2008 Elsevier Inc. All rights reserved.