PARK2

PARK2 is a human gene that encodes the Parkin protein, an E3 ubiquitin ligase of the RBR family. Parkin is approximately 465 amino acids in length and contains an N-terminal ubiquitin-like (UBL) domain, followed by RING0, RING1, IN-Between-RING (IBR), and RING2 domains. The gene is located on chromosome 6 and is broadly expressed, with relatively high expression in brain regions affected by Parkinson's disease.

Parkin participates in tagging substrate proteins with ubiquitin, targeting them for proteasomal degradation. It also plays a central role in mitochondrial quality control; upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane, phosphorylates Parkin and ubiquitin, activating Parkin's ligase activity. Activated Parkin ubiquitinates multiple outer mitochondrial membrane proteins, promoting mitophagy and clearance of damaged mitochondria.

Mutations that disrupt Parkin function cause autosomal recessive juvenile Parkinsonism, one of the most common genetic forms of early-onset Parkinson's disease. Biallelic PARK2 mutations (deletions, duplications, missense or truncating mutations) lead to parkinsonism with onset often before age 40; some individuals present later. Heterozygous PARK2 mutations may contribute to disease risk in combination with other factors, but their role is less clear.

PARK2/Parkin status is tested in genetic panels for early-onset Parkinson's disease. Research focuses on restoring Parkin function or enhancing mitophagy as potential therapeutic strategies.