Fares Bassil1,2, Paul A Guerin1,2, Nathalie Dutheil1,2, Qin Li3,4, Matthias Klugmann5, Wassilios G Meissner1,2,6,7, Erwan Bezard1,2,3,4, Pierre-Olivier Fernagut1,2. 1. Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. 2. CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. 3. China Academy of Medical Sciences, Institute of Lab Animal Sciences, Beijing, China. 4. Motac neuroscience Ltd, Manchester, United Kingdom. 5. Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia. 6. Service de Neurologie, CHU de Bordeaux, Bordeaux, France. 7. Centre de référence atrophie multisystématisée, CHU de Bordeaux, Bordeaux, France.
Abstract
BACKGROUND: MSA is a fatal neurodegenerative disorder characterized by a combination of autonomic dysfunction, cerebellar ataxia, and l-dopa unresponsive parkinsonism. The hallmark of MSA is the accumulation of α-synuclein, forming cytoplasmic inclusions in oligodendrocytes. Adeno-associated viruses allow efficient targeting of disease-associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of α-synuclein in the substantia nigra in the context of PD. OBJECTIVES: We aimed to develop viral-based models of MSA. METHODS: Chimeric viral vectors expressing either human wild-type α-synuclein or green fluorescent protein under the control of mouse myelin basic protein were injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor assessment before histopathological analysis at 3 and 6 months. RESULTS: Injection of vectors expressing α-synuclein in the striatum resulted in >80% oligodendroglial selectivity in rats and >60% in monkeys. Rats developed progressive motor deficits that were l-dopa unresponsive when assessed at 6 months. Significant loss of dopaminergic neurons occurred at 3 months, further progressing at 6 months, together with a loss of striatal neurons. Prominent α-synuclein accumulation, including phosphorylated and proteinase-K-resistant α-synuclein, was detected in the striatum and substantia nigra. CONCLUSIONS: Viral-mediated oligodendroglial expression of α-synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how α-synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies.
BACKGROUND: MSA is a fatal neurodegenerative disorder characterized by a combination of autonomic dysfunction, cerebellar ataxia, and l-dopaunresponsive parkinsonism. The hallmark of MSA is the accumulation of α-synuclein, forming cytoplasmic inclusions in oligodendrocytes. Adeno-associated viruses allow efficient targeting of disease-associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of α-synuclein in the substantia nigra in the context of PD. OBJECTIVES: We aimed to develop viral-based models of MSA. METHODS: Chimeric viral vectors expressing either human wild-type α-synuclein or green fluorescent protein under the control of mousemyelin basic protein were injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor assessment before histopathological analysis at 3 and 6 months. RESULTS: Injection of vectors expressing α-synuclein in the striatum resulted in >80% oligodendroglial selectivity in rats and >60% in monkeys. Rats developed progressive motor deficits that were l-dopa unresponsive when assessed at 6 months. Significant loss of dopaminergic neurons occurred at 3 months, further progressing at 6 months, together with a loss of striatal neurons. Prominent α-synuclein accumulation, including phosphorylated and proteinase-K-resistant α-synuclein, was detected in the striatum and substantia nigra. CONCLUSIONS: Viral-mediated oligodendroglial expression of α-synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how α-synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies.
Authors: Kalpana M Merchant; Jesse M Cedarbaum; Patrik Brundin; Kuldip D Dave; Jamie Eberling; Alberto J Espay; Samantha J Hutten; Monica Javidnia; Johan Luthman; Walter Maetzler; Liliana Menalled; Alyssa N Reimer; A Jon Stoessl; David M Weiner Journal: J Parkinsons Dis Date: 2019 Impact factor: 5.568