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Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate
Nadine Mestre-Francés, … , Jean-Michel Verdier, Eric J. Kremer
Nadine Mestre-Francés, … , Jean-Michel Verdier, Eric J. Kremer
Published July 25, 2018
Citation Information: JCI Insight. 2018;3(14):e98202. https://doi.org/10.1172/jci.insight.98202.
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Research Article Neuroscience

Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate

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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.

Authors

Nadine Mestre-Francés, Nicolas Serratrice, Aurélie Gennetier, Gina Devau, Sandra Cobo, Stéphanie G. Trouche, Pascaline Fontès, Charleine Zussy, Philippe De Deurwaerdere, Sara Salinas, Franck J.D. Mennechet, Julien Dusonchet, Bernard L. Schneider, Isabella Saggio, Vasiliki Kalatzis, M. Rosario Luquin-Piudo, Jean-Michel Verdier, Eric J. Kremer

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Figure 3

Coxsackievirus and adenovirus receptor expression in the M.

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Coxsackievirus and adenovirus receptor expression in the M.

murinusbrai...
murinusbrain. (A) Immunoblot analyses of coxsackievirus and adenovirus receptor (CAR) from the brains of M. murinus (n = 2 animals). β-Tubulin levels were used to normalize loading. (B) CAR levels in synaptosomes prepared from the cortex (n = 2 animals) and assayed for the presence of CAR. As a control, we used synaptophysin, a prototypic synapse protein. (C) CAR expression pattern, as assayed by immunofluorescence staining: SN, pyriform cortex, and thalamus (n = 3 animals). The 16-micron-thick floating sections were coincubated an anti-Tuj1 (β-III tubulin) antibody to identify neurons and with DAPI to label nuclei. Scale bar: 50 μm.

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