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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 4

Transcriptional profiles of the most discriminant genes in the striatum, in the frontal lobe, and in the midbrain after HD-GFP injection.

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Transcriptional profiles of the most discriminant genes in the striatum,...
Hierarchical clustering was obtained for each brain region: (A) right frontal cortex; (B) left frontal cortex; (C) injected (right) striatum; (D) contralateral striatum; (E) right midbrain; and (F) left midbrain. Each column corresponds to one animal, whereas each row corresponds to one gene (red: overexpressed genes; green: downregulated genes; black: genes without expression changes). Principal component analysis (PCA) of the 19–45 genes sorted by SAM or by ANOVA for each brain region analyzed. The x axis corresponds to the principal component 1 and the y axis to the principal component 2 (expressed in percentages). Projection of the individuals shows that each group of animal can be distinguished from the other irrespective of the brain structure. At the bottom of the figure, there is a schematic representation of the M. Murinus brain, indicating vector transport from the injected site, the right striatum, to the contralateral side (red hatched arrow), to the frontal cortex (blue arrow), and to the midbrain (green arrow). Brains were collected at 1 or 24 days after injection.

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ISSN 2379-3708

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