In vivo susceptibility to energy failure parkinsonism and LRRK2 kinase activity

Salvatore Novello, Daniela Mercatelli, Federica Albanese, Chiara Domenicale, Alberto Brugnoli, Elisabetta D'Aversa, Silvia Vantaggiato, Sandra Dovero, Valentina Murtaj, Luca Presotto, Monica Borgatti, Derya R. Shimshek, Erwan Bezard, Rosa Maria Moresco, Sara Belloli, Michele Morari
Neurobiology of Disease. 2022-01-01; 162: 105579
DOI: 10.1016/j.nbd.2021.105579

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1. Neurobiol Dis. 2022 Jan;162:105579. doi: 10.1016/j.nbd.2021.105579. Epub 2021 Dec
3.

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

Novello S(1), Mercatelli D(2), Albanese F(3), Domenicale C(4), Brugnoli A(5),
D’Aversa E(6), Vantaggiato S(7), Dovero S(8), Murtaj V(9), Presotto L(10),
Borgatti M(11), Shimshek DR(12), Bezard E(13), Moresco RM(14), Belloli S(15),
Morari M(16).

Author information:
(1)Department of Neuroscience and Rehabilitation, University of Ferrara, 44121
Ferrara, Italy. Electronic address: .
(2)Department of Neuroscience and Rehabilitation, University of Ferrara, 44121
Ferrara, Italy; Technopole of Ferrara, LTTA Laboratory for Advanced Therapies,
44121 Ferrara, Italy. Electronic address: .
(3)Department of Neuroscience and Rehabilitation, University of Ferrara, 44121
Ferrara, Italy. Electronic address: .
(4)Department of Neuroscience and Rehabilitation, University of Ferrara, 44121
Ferrara, Italy. Electronic address: .
(5)Department of Neuroscience and Rehabilitation, University of Ferrara, 44121
Ferrara, Italy. Electronic address: .
(6)Department of Life Science and Biotechnology, University of Ferrara, 44121
Ferrara, Italy. Electronic address: .
(7)Department of Neuroscience and Rehabilitation, University of Ferrara, 44121
Ferrara, Italy.
(8)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: .
(9)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: .
(10)Nuclear Medicine Department, San Raffaele Scientific Institute, Milan, Italy.
Electronic address: .
(11)Department of Life Science and Biotechnology, University of Ferrara, 44121
Ferrara, Italy. Electronic address: .
(12)Department of Neuroscience, Novartis Institutes for BioMedical Research,
Novartis Pharma AG, 4002 Basel, Switzerland. Electronic address:
.
(13)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: .
(14)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: .
(15)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: .
(16)Department of Neuroscience and Rehabilitation, University of Ferrara, 44121
Ferrara, Italy. Electronic address: .

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 [18F]-VC701 revealed a similar TSPO binding in MPTP-treated wild-type and
G2019S knock-in mice which was consistent with an increased GFAP striatal
expression as revealed by Real Time PCR. We conclude that LRRK2 G2019S, likely
through enhanced kinase activity, confers greater susceptibility to mitochondrial
toxin-induced parkinsonism. LRRK2 kinase inhibitors are neuroprotective in this
model.

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

 

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