Activation of mutant protein kinase Cgamma leads to aberrant sequestration and impairment of its cellular function.
Mutations in protein kinase Cgamma (PKCgamma) cause the neurodegenerative disease spinocerebellar ataxia type 14 (SCA14). In this study, expression of an extensive panel of known SCA14-associated PKCgamma 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 PKCgamma 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 PKCgamma activity due its aberrant sequestration in the early endosome compartment.
Doran
Graeme
G
MRC Functional Genetics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
Davies
Kay E
KE
Talbot
Kevin
K
D000818:Animals; D002460:Cell Line; D011992:Endosomes / Q000201:enzymology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D009154:Mutation; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000201:enzymology; D020754:Spinocerebellar Ataxias / Q000201:enzymology* / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000032:analysis
D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C087857:protein kinase C gamma; D011493:Protein Kinase C