1. Genetic elimination of dopamine vesicular stocks in the nigrostriatal pathway replicates Parkinson’s disease motor symptoms without neuronal degeneration in adult mice
- Author
-
Chloé Guinaudie, Léa C. Perret, Quentin Rainer, Bruno Giros, Alain Gratton, Luc Moquin, Elsa Isingrini, Research Center of the Douglas Mental Health University Institute, Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Psychiatry [Montreal, Quebec, Canada], McGill University- Douglas Mental Health Research Center [Montréal Quebec, Canada], Neuroscience Paris Seine ( NPS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), HAL-UPMC, Gestionnaire, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS)
- Subjects
Male ,0301 basic medicine ,Pathology ,MESH: Integrases ,Parkinson's disease ,Dopamine ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Gene Expression ,Nigrostriatal pathway ,lcsh:Medicine ,MESH: Vesicular Monoamine Transport Proteins ,MESH: Dependovirus ,MESH: Eating ,MESH: Corpus Striatum ,Eating ,Mice ,0302 clinical medicine ,MESH: Dopaminergic Neurons ,Monoaminergic ,MESH: Animals ,lcsh:Science ,Multidisciplinary ,Neurodegeneration ,Dependovirus ,3. Good health ,Substantia Nigra ,medicine.anatomical_structure ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Synaptic Vesicles ,MESH: Injections, Intraventricular ,MESH: Parkinson Disease, Secondary ,MESH: Drinking ,medicine.drug ,medicine.medical_specialty ,MESH: Gene Expression ,MESH: Mice, Transgenic ,Drinking ,MESH: Substantia Nigra ,Mice, Transgenic ,MESH: Dopamine ,Biology ,Article ,MESH: Weight Loss ,03 medical and health sciences ,Weight Loss ,Genetic model ,medicine ,Animals ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Parkinson Disease, Secondary ,MESH: Mice ,Injections, Intraventricular ,Integrases ,Dopaminergic Neurons ,lcsh:R ,MESH: Synaptic Vesicles ,medicine.disease ,Corpus Striatum ,MESH: Male ,Vesicular monoamine transporter ,030104 developmental biology ,Monoamine neurotransmitter ,MESH: Gene Deletion ,Vesicular Monoamine Transport Proteins ,[ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,lcsh:Q ,Neuroscience ,Gene Deletion ,030217 neurology & neurosurgery - Abstract
International audience; The type 2 vesicular monoamine transporter (VMAT2), by regulating the storage of monoamines transmitters into synaptic vesicles, has a protective role against their cytoplasmic toxicity. Increasing evidence suggests that impairment of VMAT2 neuroprotection contributes to the pathogenesis of Parkinson's disease (PD). Several transgenic VMAT2 mice models have been developed, however these models lack specificity regarding the monoaminergic system targeting. To circumvent this limitation, we created VMAT2-KO mice specific to the dopamine (DA) nigrostriatal pathway to analyze VMAT2's involvement in DA depletion-induced motor features associated to PD and examine the relevance of DA toxicity in the pathogenesis of neurodegeneration. Adult VMAT2 floxed mice were injected in the substancia nigra (SN) with an adeno-associated virus (AAV) expressing the Cre-recombinase allowing VMAT2 removal in DA neurons of the nigrostriatal pathway solely. VMAT2 deletion in the SN induced both DA depletion exclusively in the dorsal striatum and motor dysfunction. At 16 weeks post-injection, motor symptoms were accompanied with a decreased in food and water consumption and weight loss. However, despite an accelerating death, degeneration of nigrostriatal neurons was not observed in this model during this time frame. This study highlights a non-cytotoxic role of DA in our genetic model of VMAT2 deletion exclusively in nigrostriatal neurons. Parkinson's disease (PD), is one of the most common neurodegenerative disorders affecting 1–2% of individuals older than 65 years old worldwide 1. PD is a progressive disorder clinically characterized by a large number of motor features in particular rest tremor, bradykinesia, rigidity and loss of postural reflexes 2,3. At the pathological level, processes leading to PD begin before the appearance of the typical motor symptoms, and by the time the disease is diagnosed about 70–80% of striatal dopamine (DA) is depleted and one third of substantia nigra (SN) DA neurons and striatal DA fibers are already lost 2,4–7. Understanding the biochemical markers relevant to the pathogenesis of neurodegeneration in PD remain essential. Oxidative stress contribution to PD neurodegeneration is currently well established 8. Post-mortem studies have shown an imbalance between reactive oxygen species (ROS) production and the antioxidant protective system resulting in oxidative stress in the SN of PD patients 9,10. Superoxide (O 2−), hydrogen peroxide (H 2 O 2), and the hydroxyl radical (OH •), three important ROS in mammalian cells, can damage macromolecules including nucleic acids, lipids and proteins, leading to DA neuron degeneration, and neuron network dysfunction, ultimately progressing to PD 11. For a better understanding of the oxidative stress mechanisms in PD, the MPTP
- Published
- 2017