The Landscape of Parkin Variants Reveals Pathogenic Mechanisms and Therapeutic Targets in PD
Mutations in Parkin (PARK2) are the most common genetic cause of early-onset Parkinsons disease (PD). Parkin encodes an E3 ubiquitin ligase implicated in the turnover of damaged mitochondria. Hundreds of Parkin missense variants have been reported in public databases, yet the role of most of them in PD remains unclear. We analyzed Parkin variants using clinical, experimental, and structural modeling approaches. For most variants, clinical evidence alone was insufficient to determine pathogenicity. Utilizing a cell model that allows measurement of Parkin-mediated mitophagy and Parkin stability, 51 variants were classified into five groups based on their effect on Parkin function. Most variants were like wildtype but, unexpectedly, several enhanced mitophagy. A minority destabilized Parkin or severely disrupted Parkin-mediated mitophagy, most of which were also determined as pathogenic based on clinical evidence alone. Structural simulation predicted discrete mechanisms explaining both increases and decreases in Parkin function. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally-occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. These findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets for genotype-specific drug design.