Presenilins at the crossroad of a functional interplay between PARK2/PARKIN and PINK1 to control mitophagy: Implication for neurodegenerative diseases

Autophagic and mitophagic defects are consistently observed in Alzheimer's disease-affected brains. However, the mechanistic defects underlying these anatomical lesions remained unexplained. We have delineated a molecular cascade by which PSEN1 and PSEN2 (presenilins 1 and 2) control PINK1 transcription and function by an AICD-mediated FOXO3a-dependent mechanism. Further, we establish that PARK2 (parkin) acts upstream to PINK1 and regulates its function by a PSEN-dependent mechanism. Our study thus demonstrates a functional interplay between PSEN and PINK1 and establishes a feedback process by which PARK2 and PINK1 could control mitochondrial dysfunction and autophagic processes in various neurodegenerative pathologies including Alzheimer's and Parkinson's diseases.