LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson’s disease
Autor: | Suzanne Lesage, Philip M Beart, Adeline Muscat, Fiona Bonello, Sidi-Mohamed Hassoun, Alexis Brice, Olga Corti, François Mouton-Liger, Jean-Christophe Corvol, Christelle Tesson, Yea Seul Shin, Johannes Krupp |
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Přispěvatelé: | Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Melbourne, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Gestionnaire, Hal Sorbonne Université, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP] |
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Adult
Male Carbonyl Cyanide m-Chlorophenyl Hydrazone Ubiquitin-Protein Ligases [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Primary Cell Culture PINK1 Mitochondrion Biology [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 medicine.disease_cause Parkin 03 medical and health sciences 0302 clinical medicine Mitophagy Fluorescence Resonance Energy Transfer Genetics medicine Humans Phosphorylation Kinase activity Molecular Biology Genetics (clinical) Aged 030304 developmental biology Benzodiazepinones 0303 health sciences Mutation [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Parkinson Disease General Medicine Fibroblasts Middle Aged LRRK2 Mitochondria Cell biology nervous system diseases Pyrimidines [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Female Mitochondrial fission Protein Kinases 030217 neurology & neurosurgery |
Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2019, 28 (10), pp.1645-1660. ⟨10.1093/hmg/ddz004⟩ Human Molecular Genetics, 2019, 28 (10), pp.1645-1660. ⟨10.1093/hmg/ddz004⟩ |
ISSN: | 0964-6906 1460-2083 |
Popis: | International audience; 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 mitochondrial aggregation and attenuated mitochondrial clearance in cells coexpressing Parkin and exposed to the protonophore carbonylcyanide m-chlorophenylhydrazone. Förster resonance energy transfer imaging microscopy showed that LRRK2 impaired the interactions between Parkin and Drp1 and their mitochondrial targets early in mitophagy. The inhibition of LRRK2 kinase activity by a 'kinase-dead' LRRK2 mutation or with a pharmacological inhibitor (LRRK2-IN-1) restored these interactions. The monitoring of mitophagy in human primary fibroblasts with the novel dual-fluorescence mtRosella reporter and a new hypothermic shock paradigm revealed similar defects in PD patients with the G2019S LRRK2 substitution or PARK2 mutations relative to healthy subjects. This defect was restored by LRRK2-IN-1 treatment in LRRK2 patients only. Our results suggest that PD forms due to LRRK2 and PARK2 mutations involve pathogenic mechanisms converging on PINK1/Parkin-dependent mitophagy. |
Databáze: | OpenAIRE |
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