LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson's disease
Fiona Bonello, Sidi-Mohamed Hassoun, Francois Mouton-Liger, Yea Seul Shin, Adeline Muscat, Christelle Tesson, Suzanne Lesage, Philip M Beart, Alexis Brice, Johannes Krupp, Jean-Christophe Corvol, Olga Corti
Human Molecular Genetics | OXFORD UNIV PRESS | Published : 2019
Mutations of LRRK2, encoding leucine-rich repeat kinase 2 (LRRK2), are the leading cause of autosomal dominant Parkinson's disease (PD). The most frequent of these mutations, G2019S substitution, increases kinase activity, but it remains unclear how it causes PD. Recent studies suggest that LRRK2 modulates mitochondrial homeostasis. Mitochondrial dysfunction plays a key role in the pathogenesis of autosomal recessive PD forms linked to PARK2 and PINK1, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial kinase PINK1, which jointly regulate mitophagy. We explored the role of LRRK2 and its kinase activity in PINK1/Parkin-dependent mitophagy. LRRK2 increased mitochon..View full abstract
Awarded by Innovative Medicines Initiative Joint Undertaking
Awarded by Investissements d'Avenir
Institut National de la Sante et la Recherche Medicale (INSERM), Ipsen Laboratories, Association France Parkinson, the Innovative Medicines Initiative Joint Undertaking (grant agreement no. 115568), including financial contributions from the European Union Seventh Framework Programme (FP7/2007-2013), European Federation of Pharmaceutical Industries and Associations (EFPIA) and 'Investissements d'Avenir' ANR-10-IAIHU-06; Association Nationale Recherche Technologie and Association France Parkinson (to F.B.); the International Union of Biochemistry and Molecular Biology (to Y.S.S., Wood-Whelan Research Fellowship).