The role of parkin in familial and sporadic Parkinson's disease

Abstract

Mutations in parkin are the second most common known cause of Parkinson's disease (PD). Parkin is an ubiquitin E3 ligase that monoubiquitinates and polyubiquitinates proteins to regulate a variety of cellular processes. Loss of parkin's E3 ligase activity is thought to play a pathogenic role in both inherited and sporadic PD. Here, we review parkin biology and pathobiology and its role in the pathogenesis of PD.

Figure 1

Parkin is multifunctional ubiquitin E3 ligase. Parkin functions in the ubiquitin proteasome system as an E3 ligase. Ubiquitination requires the E1 activating enzyme and the E2 conjugating enzyme. Parkin utilizes a variety of E2s including UBCH7, UBCH8 and UbcH13/Uev1. Parkin utilizes a variety of linkages including monoubiquitination and polyubiquitanation via lysine-48 and lysine-63 chains.

Figure 2

Parkin inactivation plays a role in both sporadic Parkinson’s disease (PD)and in patients with parkin mutations. Dopaminergic (DA), nitrosative (nitric oxide – NO), oxidative (reactive oxygen species – ROS) and MPTP intoxication can inactive parkin abrogating its ubiquitination and cytoprotective properties. In sporadic PD, parkin is inactivated through nitrosative and dopaminergic stress and autosomal recessive PD it is inactivated through a variety of mutations. The loss of parkin E3 ligase activity leads to the accumulation of AIMP2 and FBP1, which causes neurodegeneration through mechanisms that require further clarification.