G2019S LRRK2 mutation facilitates α-synuclein neuropathology in aged mice.

Salvatore Novello, Ludovico Arcuri, Sandra Dovero, Nathalie Dutheil, Derya R. Shimshek, Erwan Bezard, Michele Morari
Neurobiology of Disease. 2018-12-01; 120: 21-33
DOI: 10.1016/j.nbd.2018.08.018

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1. Neurobiol Dis. 2018 Dec;120:21-33. doi: 10.1016/j.nbd.2018.08.018. Epub 2018 Aug
30.

G2019S LRRK2 mutation facilitates α-synuclein neuropathology in aged mice.

Novello S(1), Arcuri L(1), Dovero S(2), Dutheil N(2), Shimshek DR(3), Bezard
E(2), Morari M(4).

Author information:
(1)Department of Medical Sciences, Section of Pharmacology, University of
Ferrara, National Institute of Neuroscience, Ferrara, Italy.
(2)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR
5293, F-33000 Bordeaux, France.
(3)Department of Neuroscience, Novartis Institutes for BioMedical Research,
Novartis Pharma AG, 4002 Basel, Switzerland.
(4)Department of Medical Sciences, Section of Pharmacology, University of
Ferrara, National Institute of Neuroscience, Ferrara, Italy. Electronic address:
*protected email*.

Fibrillization of α-synuclein is instrumental for the development of Parkinson’s
disease (PD), thus modulating this process can have profound impact on disease
initiation/progression. Here, the impact of the p.G2019S mutation of leucine-rich
repeat kinase 2 (LRRK2), which is most frequently associated with familial and
sporadic PD, on α-synuclein pathology was investigated. G2019S knock-in mice and
wild-type controls were injected with a recombinant adeno-associated viral vector
serotype 2/9 (AAV2/9) overexpressing human mutant p.A53T α-synuclein
(AAV2/9-hα-syn). Control animals were injected with AAV2/9 carrying green
fluorescent protein. Motor behavior, transgene expression, α-syn and pSer129
α-syn load, number of nigral dopamine neurons and density of striatal
dopaminergic terminals were evaluated. To investigate the effect of aging,
experiments were performed in 3- and 12-month-old mice, evaluated 20 and 12 weeks
after virus injection, respectively. hα-syn overexpression induced progressive
motor deficits, loss of nigral dopaminergic neurons and striatal terminals, and
appearance of proteinase K-resistant aggregates of pSer129 α-syn in both young
and old mice. Although no genotype difference was observed in 3-month-old mice,
degeneration of nigral dopaminergic neurons was higher in 12-month-old G2019S
knock-in mice compared with age-matched wild-type controls (-55% vs -39%,
respectively). Consistently, a two-fold higher load of pSer129 α-syn aggregates
was found in 12-month-old G2019S knock-in mice. We conclude that G2019S LRRK2
facilitates α-synucleinopathy and degeneration of nigral dopaminergic neurons,
and that aging is a major determinant of this effect.

Copyright © 2018 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.nbd.2018.08.018
PMID: 30172844


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