β-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog–Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models
- Creators
- Goiran, Thomas
- Duplan, Eric
- Chami, Mounia
- Bourgeois, Alexandre
- El Manaa, Wejdane
- Rouland, Lila
- Dunys, Julie
- Lauritzen, Inger
- You, Han
- Stambolic, Vuk
- Biferi, Maria-Grazia
- Barkats, Martine
- Pimplikar, Sanjay
- Sergeant, Nicolas
- Colin, Morvane
- Morais, Vanessa
- Pardossi-Piquard, Raphaëlle
- Checler, Frédéric
- Alves da Costa, Cristine
- Others:
- Institut de pharmacologie moléculaire et cellulaire (IPMC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
- Centre de recherche en Myologie – U974 SU-INSERM ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
- Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc) ; Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille
- Institut de pharmacologie moléculaire et cellulaire (IPMC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
Description
BACKGROUND: Mitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer's disease-affected brains by yet unexplained mechanisms. METHODS: We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which presenilins control phosphatase and tensin homolog-induced kinase 1 (Pink-1) expression and transcription. In vivo approaches were carried out on various transgenic and knockout animals as well as in adeno-associated virus-infected mice. Functional readout and mitochondrial physiology (mitochondrial potential) were assessed by combined procedures including flow cytometry, live imaging analysis, and immunohistochemistry. RESULTS: We show that presenilins 1 and 2 trigger opposite effects on promoter transactivation, messenger RNA, and protein expression of Pink-1. This control is linked to g-secretase activity and b-amyloid precursor protein but is independent of phosphatase and tensin homolog. We show that amyloid precursor protein intracellular domain (AICD) accounts for presenilin-dependent phenotype and upregulates Pink-1 transactivation in cells as well as in vivo in a Forkhead box O3a-dependent manner. Interestingly, the modulation of g-secretase activity or AICD expression affects Pink-1-related control of mitophagy and mitochondrial dynamics. Finally, we show that parkin acts upstream of presenilins to control Pink-1 promoter transactivation and protein expression. CONCLUSIONS: Overall, we delineate a molecular cascade presenilins-AICD-Forkhead box O3a linking parkin to Pink-1. Our study demonstrates AICD-mediated Pink-1-dependent control of mitochondrial physiology by presenilins. Furthermore, it unravels a parkin-Pink-1 feedback loop controlling mitochondrial physiology that could be disrupted in neurodegenerative conditions.
Abstract
International audience
Additional details
- URL
- https://hal.archives-ouvertes.fr/hal-02360864
- URN
- urn:oai:HAL:hal-02360864v1
- Origin repository
- UNICA