Alternative Translation Initiation in PRKN Delays the Onset of Parkinson's Disease and Offers a Therapeutic Target

Objective: Biallelic variants in PRKN cause autosomal recessive Parkinson's disease (PD) with a median age at onset of 31 years. When evaluating the 16 previously published carriers of a homozygous deletion of Exon 2 from the International Parkinson's Disease and Movement Disorder Society Gene Database (MDSGene) database, the median age at onset is later (39.5 years) than in carriers of other PRKN pathogenic variants. We investigated whether these carriers show delayed disease onset compared with carriers of other pathogenic PRKN variants and explored the underlying molecular mechanism. Methods: We compared 26 homozygous PRKN Exon 2 deletion carriers with carriers of other pathogenic variants. Using human-induced pluripotent stem cell (hiPSC)-derived neuronal cell models from an unaffected 86-year-old carrier, genome-edited control lines, neuroblastoma cell lines, and in silico prediction, we investigated the underlying mechanism. Results: Patients with PRKN Exon 2 deletions showed a later age at onset compared with carriers of other pathogenic variants. We discovered elevated levels of an N-terminally truncated Parkin proteoform lacking amino acids 1-79 due to internal translation initiation. This truncated protein partially retained ubiquitin ligase activity at endogenous levels. Treatment with Parkin modulator BIO-2007817 enhanced this residual function but reduced endogenous full-length Parkin activity. Interpretation: Residual truncated Parkin function provides a molecular explanation for a delayed disease onset in PRKN Exon 2 deletion carriers. Whereas this retained activity can be pharmacologically enhanced, the modulator's inhibitory effect on endogenous full-length Parkin may mandate strict patient stratification based on genotype. This finding offers mutation-specific counseling opportunities and highlights a potential therapeutic approach for appropriately selected patients with PARK-PRKN. ANN NEUROL 2026;99:1379-1393.