Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate

Nadine Mestre-Francés 1 Nicolas Serratrice Aurélie Gennetier 2 Gina Devau 1 Sandra Cobo 3 Stephanie Trouche 1 Pascaline Fontes 4 Charleine Zussy 5 Philippe de Deurwaerdère 6 Sara Salinas 7 Franck Jd Mennechet 5 Julien Dusonchet Bernard Schneider 8 Isabella Saggio 9 Vasiliki Kalatzis 10 M Rosario Luquin-Piudo Jean-Michel Verdier 1 Eric Kremer 5 Franck J.D. Mennechet M. Rosario Luquin-Piudo
1 MMDN - Mécanismes moléculaires dans les démences neurodégénératives
2 Physiopathologie des Maladies du Système Nerveux Central
3 SysDiag - Sysdiag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic
4 IRIM - Institut de Recherche en Infectiologie de Montpellier
5 IGMM - Institut de Génétique Moléculaire de Montpellier
6 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
7 Pathogénèse et contrôle des infections chroniques (PCCI)
8 Institut de géologie Dolomieu
9 Università degli Studi di Roma "La Sapienza" [Rome]
10 INM - Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs
Abstract : Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among the elderly. To understand its pathogenesis and to test therapies, animal models that faithfully reproduce key pathological PD hallmarks are needed. As a prelude to developing a model of PD, we tested the tropism, efficacy, biodistribution, and transcriptional effect of canine adenovirus type 2 (CAV-2) vectors in the brain of Microcebus murinus, a nonhuman primate that naturally develops neurodegenerative lesions. We show that introducing helper-dependent (HD) CAV-2 vectors results in long-term, neuron-specific expression at the injection site and in afferent nuclei. Although HD CAV-2 vector injection induced a modest transcriptional response, no significant adaptive immune response was generated. We then generated and tested HD CAV-2 vectors expressing leucine-rich repeat kinase 2 (LRRK2) and LRRK2 carrying a G2019S mutation (LRRK2G2019S), which is linked to sporadic and familial autosomal dominant forms of PD. We show that HD-LRRK2G2019S expression induced parkinsonian-like motor symptoms and histological features in less than 4 months.
Keywords : Neurodegeneration Neuroscience Parkinson’s disease
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https://hal.umontpellier.fr/hal-01977711
Contributeur : Nadine Mestre-Frances <>
Soumis le : vendredi 11 janvier 2019 - 08:14:13
Dernière modification le : vendredi 19 juillet 2019 - 01:11:05

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UNIV-MONTPELLIER | CNRS | PMSNC | EPHE | MMDN | PSL | BS | UGA | SORBONNE-UNIVERSITE | PCCI

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Nadine Mestre-Francés, Nicolas Serratrice, Aurélie Gennetier, Gina Devau, Sandra Cobo, et al.. Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate. JCI Insight, American Society for Clinical Investigation, 2018, 3 (14), ⟨10.1172/jci.insight.98202⟩. ⟨hal-01977711⟩

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