Parkin Is Dispensable for Mitochondrial Function, but Its Ubiquitin Ligase Activity Is Critical for Macroautophagy and Neurotransmitters: Therapeutic Potential beyond Parkinson's Disease

Abstract

Parkin biology has emerged as an exciting area of pharmaceutical development for several human diseases, including cancer and neurodegeneration. Parkin's role is multifaceted in human health and disease and its function affecting major cellular quality control mechanisms, including the ubiquitin-proteasome and autophagy-lysosome systems, is critical in the maintenance of cellular homeostasis. Loss of Parkin function due to aging, protein instability and gene mutations is manifest in a number of human diseases, contributing to the validation of this protein as a therapeutic target. Parkin activation to mobilize cellular quality control mechanisms and counteract dyshomeostasis is a highly desirable area for therapeutic development. The elucidation of Parkin's crystal structure and better understanding of possible posttranslational modifications (i.e. phosphorylation, ubiquitination, etc.) that regulate Parkin's enzymatic activity suggest that this protein is a therapeutic drug target in many human diseases. Here we review Parkin's role in health and disease and discuss the effects of self-ubiquitination and deubiquitination on Parkin activity. This review provides further evidence showing the longitudinal effects of Parkin deletion on mitochondrial function, oxidative stress and neurotransmitter balance in vivo using high-frequency ¹H/¹³C NMR spectroscopy.