Journal
BIOLOGICAL PSYCHIATRY
Volume 83, Issue 5, Pages 416-427Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2017.04.011
Keywords
AICD; FOXO3a; gamma-Secretase; Mitochondrial dysfunction; Mitophagy; Parkin; Pink-1; Presenilins; 3xTgAD Mice
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Funding
- Conseil departemental des Alpes Maritimes
- Foundation Claude Pompidou
- LABEX (Laboratory of Excellence, Investments for the Future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease)
- Hospital University Federation OncoAge
- Ligue Contre le Cancer
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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 gamma-secretase activity and beta-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.
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