PARK2Parkin

PARK2, also known as parkin, encodes Parkin, a cytosolic E3 ubiquitin ligase of the RING-between-RING (RBR) family. Parkin includes an N-terminal ubiquitin-like (UBL) domain and RING domain motifs (RING0, RING1, IBR, RING2) that coordinate ubiquitin transfer. In healthy cells Parkin is largely autoinhibited; after mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane, phosphorylates Parkin and ubiquitin, and activates Parkin for recruitment to damaged mitochondria.

Activated Parkin ubiquitinates outer mitochondrial membrane proteins to promote mitophagy, contributing to mitochondrial quality control and turnover. This process is tightly linked with PINK1 signaling and can influence mitochondrial dynamics. Parkin also regulates broader aspects of protein homeostasis through ubiquitination of various substrates.

Mutations in PARK2 are a common cause of autosomal recessive juvenile Parkinsonism and represent a significant fraction of familial early-onset PD. Patients typically present before age 40 and often respond well to L-dopa. Pathology in parkin-related PD frequently shows dopaminergic neuron loss with fewer Lewy bodies than in sporadic PD.

Genetic alterations include missense and loss-of-function mutations, as well as exonic deletions and duplications; copy-number changes are frequent. PARK2 mutations are inherited in an autosomal recessive pattern, though some individuals harbor heterozygous variants. Research uses cellular and animal models to study Parkin-mediated mitophagy and to explore therapies aimed at enhancing mitochondrial quality control.