Parkin Regulation and Neurodegenerative Disorders

Abstract

Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the cell, particularly in neurons, are widely thought to be protective. The pivotal role that Parkin plays in maintaining neuronal survival is underscored by our current recognition that Parkin dysfunction represents not only a predominant 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 has led to an explosion of knowledge regarding its physiological roles and its relevance to PD. However, our understanding of Parkin is far from being complete. Indeed, surprises emerge from time to time that compel us to constantly update the paradigm of Parkin function. For example, we now know that Parkin's function is not confined to mere housekeeping protein quality control (QC) roles but also includes mitochondrial homeostasis and stress-related signaling. Furthermore, emerging evidence also suggest a role for Parkin in several other major neurodegenerative diseases including Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Yet, it remains truly amazing to note that a single enzyme could serve such multitude of functions and cellular roles. Clearly, its activity has to be tightly regulated. In this review, we shall discuss this and how dysregulated Parkin function may precipitate neuronal demise in various neurodegenerative disorders.

Keywords: Parkinson’s disease; autophagy; mitochondria; mitophagy; neurodegeneration; proteasome; protein misfolding; ubiquitin.

Figure 1

Structure of regulation of Parkin. Top, Schematic depiction of parkin structure. Bottom, A model of Parkin activity regulation—Under normal conditions, Parkin exists in an auto-inhibited state where access to its E2-binding RING1 site is occluded by its Ubl and repressor element of parkin (REP) domains and access to its RING2’s active site is blocked by the RING0 domain. Upon the phosphorylation Parkin’s Ubl domain by PINK1 at Serine 65 (S65) and the concomitant engagement of RING1 with phosphorylated ubiquitin, the Ubl is displaced away from RING1, which led to the structural rearrangement of the various domains of Parkin. The enzyme consequently becomes fully activated.

Figure 2

Proposed model of Parkin’s role as a triage between proteasome and autophagy degradation. Under normal cellular conditions, proteins destined for degradation by the proteasome are tagged with a chain of K48-linked ubiquitin. In times of proteolytic stress, the cell switches to K63-linked ubiquitination to divert the protein load originally targeted for proteasomal degradation away from the otherwise overloaded machinery. Parkin facilitates this switch by increasing its affinity for Ubc13 in the presence of proteasome dysfunction.

Figure 3

An updated model of PINK1/Parkin-mediated mitophagy. (1) In healthy mitochondria, there is no accumulation of PINK1 on the outer mitochondrial membrane (OMM) as the protein is rapidly imported, processed and degraded. (2) Upon mitochondrial depolarization, full length PINK1 accumulates on the OMM leading to the phosphorylation of ubiquitin on the surface of the mitochondria. This results in the recruitment of the autophagy receptors optineurin (OPTN) and NDP52 and the consequent activation of the mitophagy process, albeit at low level. (3) Parkin is also recruited to the OMM, whose latent activity becomes unmasked due to its interaction with phosphorylated ubiquitin and its phosphorylation by PINK1. (4) Activated Parkin promotes the polyubiqutination of mitochondrial substrates that in turn provides more ubiquitin substrates for PINK1 to phosphorylate. This amplifies the signal for the recruitment of autophagy receptors and results in robust mitophagy.