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Speaker at International Alzheimer’s Disease & Dementia Conference 2022 - Alves Da Costa
University of the Côte d'Azur, France
Title : Gamma-secretase mediated mitophagy control via PINK1 regulation in Alzheimer's disease


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.


Cristine Alves da Costa (CAC) is research director INSERM at IPMC-CNRS, Valbonne, France. Actually she drives a team interested in the role of Parkinson's disease associated genes in the etiology of Parkinson’s and Alzheimer’s diseases. CAC has authored more than 80 articles (research ID G-8075-2011), is reviewer of several journals and is a permanent editorial board member of several open access journals like Current Neuropharmacology and is editor in chief of Parkinson’s disease.