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
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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