Species-dependent activities of the PINK1–parkin axis

Abstract In vitro studies have established that PTEN-induced putative kinase 1 (PINK1) and parkin are central regulators of mitophagy, and loss-of-function mutations in either gene can cause early-onset Parkinson’s disease (PD). Although various animal models, including mice and pigs with PINK1 or PRKN knockout, have largely failed to recapitulate the neurodegeneration seen in PD patients, effective knockdown of PINK1 or PRKN in non-human primates, when achieving substantial protein depletion, does induce dopaminergic neuron loss in the substantia nigra and α‑synuclein pathology, suggesting that both the degree of protein loss and the species-dependent PINK1–parkin axis activity contribute to PD pathogenesis. This review compares pathological and behavioral outcomes of PINK1- and parkin-deficient animal models across species, illustrates diverse functions of the PINK1–parkin axis beyond mitophagy, discusses mechanisms underlying the species-dependent differences, and highlights the therapeutic potential of targeting this pathway. The review also underscores the necessity of considering species-specific mechanisms when investigating the PINK1/parkin pathway.