In vivo susceptibility to energy failure parkinsonism and LRRK2 kinase activity.

Animals Corpus Striatum / metabolism Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism Mice Mutation Parkinson Disease / metabolism Parkinsonian Disorders / metabolism Phosphorylation
G2019S LRRK2 LRRK2 kinase-dead LRRK2 knock-out MLi-2 MPTP PF-06447475 Parkinson's disease TSPO [(18)F]-VC701 pSer935 LRRK2

Journal

Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169

Informations de publication

Date de publication:
01 2022
Historique:
received: 21 09 2021
revised: 08 11 2021
accepted: 02 12 2021
pubmed: 7 12 2021
medline: 8 4 2022
entrez: 6 12 2021
Statut: ppublish

Résumé

The G2019S mutation of LRRK2 represents a risk factor for idiopathic Parkinson's disease. Here, we investigate whether LRRK2 kinase activity regulates susceptibility to the environmental toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). G2019S knock-in mice (bearing enhanced kinase activity) showed greater nigro-striatal degeneration compared to LRRK2 knock-out, LRRK2 kinase-dead and wild-type mice following subacute MPTP treatment. LRRK2 kinase inhibitors PF-06447475 and MLi-2, tested under preventive or therapeutic treatments, protected against nigral dopamine cell loss in G2019S knock-in mice. MLi-2 also rescued striatal dopaminergic terminal degeneration in both G2019S knock-in and wild-type mice. Immunoblot analysis of LRRK2 Serine935 phosphorylation levels confirmed target engagement of LRRK2 inhibitors. However, MLi-2 abolished phosphoSerine935 levels in the striatum and midbrain of both wild-type and G2019S knock-in mice whereas PF-06447475 partly reduced phosphoSerine935 levels in the midbrain of both genotypes. In vivo and ex vivo uptake of the 18-kDa translocator protein (TSPO) ligand [

Identifiants

DOI: 10.1016/j.nbd.2021.105579 PMID: 34871735
pubmed: 34871735
pii: S0969-9961(21)00328-4
doi: 10.1016/j.nbd.2021.105579
pii:
doi:

Substances chimiques

Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

105579

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Auteurs

Salvatore Novello (S)

Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy. Electronic address: salvatore.novello@epfl.ch.

Daniela Mercatelli (D)

Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy; Technopole of Ferrara, LTTA Laboratory for Advanced Therapies, 44121 Ferrara, Italy. Electronic address: daniela.mercatelli@unife.it.

Federica Albanese (F)

Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy. Electronic address: federica.albanese@unife.it.

Chiara Domenicale (C)

Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy. Electronic address: chiara.domenicale@unife.it.

Alberto Brugnoli (A)

Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy. Electronic address: alberto.brugnoli@unife.it.

Elisabetta D'Aversa (E)

Department of Life Science and Biotechnology, University of Ferrara, 44121 Ferrara, Italy. Electronic address: elisabetta.daversa@unife.it.

Silvia Vantaggiato (S)

Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.

Sandra Dovero (S)

Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. Electronic address: sandra.dovero@u-bordeaux.fr.

Valentina Murtaj (V)

Nuclear Medicine Department, San Raffaele Scientific Institute, Milan, Italy; PhD Program in Neuroscience, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy; Medicine and Surgery Department, University of Milano Bicocca, Monza, Italy. Electronic address: murtaj.valentina@hsr.it.

Luca Presotto (L)

Nuclear Medicine Department, San Raffaele Scientific Institute, Milan, Italy. Electronic address: presotto.luca@hsr.it.

Monica Borgatti (M)

Department of Life Science and Biotechnology, University of Ferrara, 44121 Ferrara, Italy. Electronic address: monica.borgatti@unife.it.

Derya R Shimshek (DR)

Department of Neuroscience, Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4002 Basel, Switzerland. Electronic address: derya.shimshek@novartis.com.

Erwan Bezard (E)

Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. Electronic address: erwan.bezard@u-bordeaux.fr.

Rosa Maria Moresco (RM)

Nuclear Medicine Department, San Raffaele Scientific Institute, Milan, Italy; Medicine and Surgery Department, University of Milano Bicocca, Monza, Italy; Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Italy. Electronic address: moresco.rosamaria@hsr.it.

Sara Belloli (S)

Nuclear Medicine Department, San Raffaele Scientific Institute, Milan, Italy; Medicine and Surgery Department, University of Milano Bicocca, Monza, Italy; Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Italy. Electronic address: belloli.sara@hsr.it.

Michele Morari (M)

Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy. Electronic address: m.morari@unife.it.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › In vivo susceptibility to energy failure...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Noyaux gris centraux › Corps strié › In vivo susceptibility to energy failure...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › Leucine-rich repeat serine-threonine protein kinase-2 › In vivo susceptibility to energy failure...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › In vivo susceptibility to energy failure...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › In vivo susceptibility to energy failure...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › In vivo susceptibility to energy failure...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Troubles de la motricité › Syndromes parkinsoniens › In vivo susceptibility to energy failure...
questionsmedicales.fr › Métabolisme › Phosphorylation › In vivo susceptibility to energy failure...