Parkin and ubiquitylation of cellular substrates

National Institute On Aging

Investigators

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Abstract

Parkin was the first gene found for recessive parkinsonism and the parkin protein has been shown to have activity as an E3 ubiquitin-protein ligase. Such enzymes are involved in a variety of cellular processes, prominently in the degradation of target proteins through the proteasome but also in directing of proteins to specific subcellular compartements. Parkin mutations are loss of function and presumably result in the accumulation or inappropriate behavior of its substrates. However, the critical substrates for parkin are not established. Many have been proposed, but rather few have yet been demonstrated to accumulate in vivo or to account for the effects of loss of parkin function. Therefore, and despite a significant amount of research, understanding parkin substrates is a critical challenge in the Parkinson disease field.[unreadable] We have recently shown that a novel substrate for parkin is phospholipase C-gamma 1 (PLCg1), an enzyme that catalyzes the hydrolysis of phosphoinositides (PI) to inositol triphosphate (IP3) and diacylglycerol, two second messengers that regulate the mobilization of the intracellular calcium and protein kinase C (PKC) activation respectively. Parkin controls steady state levels of PLCg1 in cells and in mouse brain; likely the same is also true for human brain. We are currently exploring how this might affect cellular function including intracellular calcium levels.[unreadable] We have also examined mitochondrial function in a different model system, that of parkin deficient fibroblast cell lines. We have found that parkin deficient cells have a distinct phenotype that would be consistent with an increased tendency of mitochondria to fragment (fission). This observation is consistent with other recessive parkinsonism genes, DJ-1 and PINK1, and may imply a common pathway between the three proteins. Whether this is true, and how this might relate to parkins function as an E3 ligase, is under active investigation.