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. 2017;13(11):2004-2005.
doi: 10.1080/15548627.2017.1363950. Epub 2017 Sep 21.

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

Frédéric Checler  1 , Thomas Goiran  1 , Cristine Alves da Costa  1
Affiliations

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

Frédéric Checler et al. Autophagy. 2017.

Abstract

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.

Keywords: AICD; Alzheimer disease; FOXO3/Foxo3a; PARK2/parkin; PINK1; Parkinson disease; in vivo; mitophagy; transcription; transgenic mice; γ-secretase.

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Figures

Figure 1.
Figure 1.
Molecular cascade linking PARK2 and PINK1. PARK2 upregulates Psen1 promoter transactivation and increases its protein and mRNA levels. PSEN1-associated γ-secretase activity targets APP thereby yielding AICD that interacts physically with FOXO3 to increase Pink1 gene transcription and protein expression. AICD lowers DNM1L/Drp1 and MFN2 (mitofusin 2), increases LC3-II and decreases SQSTM1/p62, TIMM23 (TIMM) and TOMM20 (TOMM) expression. AICD-mediated control of mitochondrial dynamics and mitophagy is totally abolished by Pink1 gene invalidation. PINK1 recruits PARK2 to damaged mitochondria. Thus, PARK2-PINK1 interplay drives the homeostasis of the 2 proteins and regulates mitochondrial dynamics and the mitophagic process that can be disrupted in pathological conditions.
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Comment on

  • Punctum to: Goiran Thomas, Duplan Eric, Chami Mounia, Bourgeois Alexandre, El Manaa Wejdane, Rouland Lila, Dunys Julie, Lauritzen Inger, You Han, Stambolic Vuk, Grazia Biféri4 Maria, Barkats Martine, Pimplikar Sanjay W., Sergeant Nicolas, Colin Morvane, Morais Vanessa A., Pardossi-Piquard Raphaelle, Checler Frédéric. and da Costa Cristine Alves. βAPP intracellular domain controls mitochondrial function by modulating Pink-1 transcription in cells and in Alzheimer mice models. Biol. Psy. 2017 May 3. pii: S0006–3223(17)31515–9. doi: 10.1016/j.biopsych.2017.04.011, in press.