Title : Gamma-secretase mediated mitophagy control via PINK1 regulation in Alzheimer's disease
Abstract:
Mitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer’s diseaseaffected brains by yet unexplained mechanisms
We show that presenilins 1 and 2 trigger opposite effects on promoter transactivation, mRNA and protein expression of PTEN-induced kinase 1 (PINK1). This control is linked to gammasecretase activity and APP but independent of PTEN. We show that APP Intracellular Domain (AICD) accounts for presenilin-dependent phenotype and up-regulates PINK1 transactivation in cells as well as in vivo in a FOXO3a-dependent manner. Interestingly, the modulation of gamma-secretase activity or AICD expression impacts PINK1 related control of mitophagy and mitochondrial dynamics. Finally, we show that parkin acts upstream of presenilins to control PINK1 promoter transactivation and protein expression.
Overall, we delineate a molecular cascade presenilins-AICD-FOXO3a linking Parkin to PINK1. Our study demonstrates an AICD-mediated PINK1-dependent control of mitochondrial physiology by presenilins. Furthermore, it unravels a parkin-PINK1 feedback loop controlling mitochondrial physiology that could be disrupted in neurodegenerative conditions.
