15 Oct 2001

Last year researchers identified a mutation in rats, the so-called agu mutation (Payne et al), which resulted in a phenotype resembling human Parkinsonism. In November's Nature Neuroscience, available online today, scientists at Wayne Davies' lab, University of Glasgow, report that the agu mutation resides in the gene for the gamma isoform of protein kinase C (Prkcg).

The researchers crossed mutant animals (AS/AGU) with wildtype Brown Norway rats and mapped the mutation using known and new chromosomal markers. They found that one of the markers was tightly linked to agu, falling within 0.03 cM of the mutation. This marker lies within the 3' untranslated region of Prkcg, indicating PKCg may underlie the Parkinsonian phenotype. When the researchers sequenced the gene from the AS/AGU animals, they found a G to T transversion that resulted in a premature stop codon predicted to truncate the protein. Western analysis of AS/AGU rat brain extracts, using an antibody directed toward the C-terminus of PKCg, confirmed the absence of wild-type protein. The antibody also failed to stain Purkinje cells of AS/AGU cerebellum.

PKC family members have been implicated in a broad spectrum of functions in neurons (Tanaka, C et al.), including dopamine release and apoptosis, but the specific roles of particular isoforms like PKCg remain largely unknown, the authors write. Identifying human PKCg-specific substrates may be a step toward elucidate the mechanism of neurodegeneration in Parkinson's disease.-Tom Fagan