Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate
JCI Insight. 2018-07-25; 3(14):
DOI: 10.1172/jci.insight.98202
Lire sur PubMed
Mestre-Francés N(1), Serratrice N(2), Gennetier A(2), Devau G(1), Cobo S(1), Trouche SG(1), Fontès P(1), Zussy C(2), De Deurwaerdere P(3), Salinas S(2), Mennechet FJ(2), Dusonchet J(4), Schneider BL(4), Saggio I(5)(6)(7), Kalatzis V(8), Luquin-Piudo MR(9)(10)(11), Verdier JM(1), Kremer EJ(2).
Author information:
(1)MMDN, University of Montpellier, Ecole Pratique des Hautes Etudes, INSERM, PSL University, Montpellier, France.
(2)Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
(3)Institut des Matériaux Jean Rouxel, CNRS, Bordeaux, France.
(4)Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
(5)Department of Biology and Biotechnology « C. Darwin, » Sapienza University of Rome, Rome, Italy.
(6)Pasteur Institute, Cenci Bolognetti Foundation, Rome, Italy.
(7)Institute of Molecular Biology and Pathology, CNR, Rome, Italy.
(8)Institute of Neurosciences of Montpellier, INSERM, University of Montpellier, Montpellier, France.
(9)Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
(10)Neurology Department, Clinica Universidad de Navarra, Pamplona, Spain.
(11)Neuroscience Division, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain.
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.