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Brain Advance Access published online on December 23, 2004
Brain, doi:10.1093/brain/awh378
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Brain © Guarantors of Brain 2004; all rights reserved
Received October 7, 2004
Revised November 22, 2004
Accepted November 23, 2004

Article

Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting

D. S. Verbeek 1, M. A. Knight 2, G. G. Harmison 2, K. H. Fischbeck 2, and B. W. Howell 2*

1 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA; Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, Netherlands
2 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA

* To whom correspondence should be addressed.
B. W. Howell, E-mail: howellb{at}ninds.nih.gov


  Abstract

Summary The protein kinase C gamma (PKC{gamma}) gene is mutated in spinocerebellar ataxia type 14 (SCA14). In this study, we investigated the effects of two SCA14 missense mutations, G118D and C150F, on PKC{gamma} function. We found that these mutations increase the intrinsic activity of PKC{gamma}. Direct visualization of labelled PKC{gamma} in living cells demonstrates that the mutant protein translocates more rapidly to selected regions of the plasma membrane in response to Ca2+ influx. These results point to specific alterations in mutant PKC{gamma} function that could lead to the selective neuronal degeneration of SCA14.

Keywords: SCA14; spinocerebellar ataxia; PKC{gamma}; Purkinje cells.
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