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Étude de la protéine PINK1 dans la maladie d'Alzheimer et le cancer cérébral

Abstract : One third of the European populations is affected by a brain disorder. Thus, Alzheimer’s disease and gliomas represent the most frequent human brain dementia syndrome and tumor type, respectively. Several epidemiological studies have shown an inverse relationship between the risk of developing a neurodegenerative disease and a brain tumor, suggesting the existence of common molecular denominators between these pathologies. Interestingly, both pathologies are characterized by a mitochondrial dysfunction. The mitochondrial kinase associated to autosomal recessive Parkinson’s disease, PINK1, is particularly implicated in the control of mitochondrial homeostasis. The main objective of my thesis was to study the molecular mechanisms underlying PINK1 gene regulation and their link with the mitochondrial dysfunction observed in either Alzheimer’s disease or gliomas. Thus, during my thesis we have examined the ability of PINK1 to control mitochondria homeostasis in an Alzheimer’s pathological context. We demonstrate that AICD, a cleavage product of the trans-membrane protein βAPP by γ-secretase, impacts mitochondrial physiology via its ability of positively controlling PINK1 transcription. In addition, we show that the signaling cascade linking γ-secretase and PINK1 is initiated by parkin transcriptional regulation of presenilins, the main component of γ-secretase catalytic complex. Finally, we also establish that the tumor suppressor p53 can negatively regulate PINK1 transcription in vitro and in vivo suggesting that the misregulated autophagic response associated to brain tumors development may be caused by defective p53-PINK1 interplay.
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Submitted on : Tuesday, January 2, 2018 - 2:00:16 AM
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  • HAL Id : tel-01674221, version 1



Thomas Goiran. Étude de la protéine PINK1 dans la maladie d'Alzheimer et le cancer cérébral. Sciences agricoles. Université Côte d'Azur, 2016. Français. ⟨NNT : 2016AZUR4153⟩. ⟨tel-01674221⟩



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