PARK2 Induces Autophagy Removal of Impaired Mitochondria via Ubiquitination
Mutations of PARK2, a gene encoding the ubiquitin ligase Parkin, are causative of autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the relentless loss of dopaminergic neurons in the midbrain. The pivotal role that Parkin plays in maintaining dopaminergic neuronal survival is underscored by our current recognition that its dysfunction not only represents a prevalent cause of familial parkinsonism but also a formal risk factor for the more common, sporadic form of Parkinson's disease (PD). Accordingly, keen research on Parkin over the past decade or so has led to a significant advancement in our knowledge regarding its physiological roles and its relevance to PD. In particular, a recent seminal discovery that identified Parkin as a key regulator of mitochondrial quality control has provided an attractive mechanism that potentially underlies mitochondrial dysfunction commonly seen in the PD brain, which is thought to be a pathogenic driver of the disease. Indeed, the finding has led to a flurry of activity to elucidate the precise molecular events underlying Parkin-mediated mitophagy that ensues to this date. However, like all newly proposed models, the current model of Parkin-mediated mitophagy remains imperfect and is continually being debated and updated. In this chapter, we shall discuss the current knowledge and controversies surrounding this exciting topic.
