Perte de fonction de la voie de signalisation <> dans la physiopathologie de la maladie de Parkinson - Mécanismes et conséquences

Abstract : Parkinson’s disease (PD) is linked to a specific loss of dopaminergic neurons of the substancia nigra. The disease is most often sporadic but familial monogenic forms exist, for example due to mutations in PARK2 or PINK1. Those genes encore the cytosolic ubiquitin-protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, both essential for mitochondrial quality control. This work studies the role of their interaction at the outer mitochondrial membrane in the regulation of mitochondrial homeostasis. We found that the association of PINK1 and Parkin to the mitochondrial import TOM complex during mitochondrial stress induces the import of most proteins targeted to mitochondria; that destabilizing this complex is sufficient to initiate mitophagy; and that Parkin activation by PINK1 facilitates the import of its substrate, HSD17β10. We developed an inducible BRET-based molecular biosensor to study the classical pre-sequence import pathway. We also found, in a neuronal model, that mitochondrial stress induced a strong increase in the expression of mitochondrial biogenesis key genes, in the presence of Parkin; and that these genes are basally up-regulated in PARK2-/- neurons, possibly reflecting an alteration of acute stress response. These results increase our understanding of the pathophysiology of autosomal recessive forms of PD, underlining the importance of the PINK1/Parkin pathway in mitochondrial import and biogenesis.
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Maxime Jacoupy. Perte de fonction de la voie de signalisation <> dans la physiopathologie de la maladie de Parkinson - Mécanismes et conséquences. Neurobiologie. Université Pierre et Marie Curie - Paris VI, 2016. Français. ⟨NNT : 2016PA066387⟩. ⟨tel-01878349⟩

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