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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 6

Changes in TH cell characteristics following LRRK2G2019S expression.

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Changes in TH cell characteristics following LRRK2G2019S expression.
Rep...
Representative images of (A) tyrosine hydroxylase (TH) immunoreactivity (dark brown staining) in a coronal section of the midbrain of LRRK2G2019S-expressing M. murinus (n = 8 animals). High-magnification images of TH+ cell bodies and projections in the hemisphere expressing LRRK2G2019S (left) versus the contralateral hemisphere (right) are shown below. Scale bars: 1 mm (top); 50 μm (bottom). (B) Swollen neurites and (C) dystrophic neurons due to LRRK2G2019S expression. (D) Neurons in control animals (n = 2). (E) Loss of neurites and (F) TH immunoreactivity due to LRRK2G2019S expression. Scale bars: 2.5 mm. (G) Quantification of TH+ cells in the substantia nigra of the LRRK2G2019S-expressing hemisphere versus controls (n = 3 mock-, 5 HD-GFP–, 7 HD-LRRK2G2019S–, and 4 HD-LRRK2-injected animals). TH+ neurons were quantified by counting cells in 1 of every 6 sections. The y axis represents the average number of TH+ neurons/section in all groups. Mann-Whitney test: *P < 0.05. (H) optical density of TH immunoreactivity in the putamen (n = 4 animals). (I) Optical density of TH immunoreactivity in the caudate nucleus (n = 3 animals). Data in H and I are expressed as mean ± SEM. Nonparametric Kruskal-Wallis test: *P < 0.05. C, caudate nucleus; P, putamen.

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