ELUCIDATING THE ROLE OF CYTOSOLIC PINK1 IN PARKINSON'S DISEASE

Abstract

The function of PINK1 has been a subject of intense investigations due to its role as a genetic contributor of Parkinson’s disease (PD). Comparatively, the function of the cytosolic form of PINK1 (PINK1Δ104) is often overlooked. We demonstrated in PINK1-deficient HeLa cells that the expression of cytosolic PINK1Δ104 alone is sufficient to promote ubiquitin phosphorylation and Parkin’s translocation to the mitochondria to trigger mitophagy. Moreover, we showed in the Drosophila model system that PINK1Δ104 expression alone can rescue the muscle and neuron-associated phenotypes of PINK1 loss-of-function flies. Thus, suggesting that the two forms of PINK1 functionally converge to maintain mitochondrial quality control both in vitro and in vivo. Importantly, PINK1Δ104 disease-associated mutants were impaired in mediating the above phenomena, suggesting the importance of kinase activity for PINK1Δ104’s function. Taken together, our results revealed the physiological and patho-physiological relevance of PINK1Δ104, emphasising the need to understand this oft-overlooked PINK1 species better.