Viral-Mediated Oligodendroglial Alpha-Synuclein Expression Models Multiple System Atrophy

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 alpha-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 alpha-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 alpha-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 alpha-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 alpha-synuclein accumulation, including phosphorylated and proteinase-K-resistant alpha-synuclein, was detected in the striatum and substantia nigra. Conclusions: Viral-mediated oligodendroglial expression of alpha-synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how alpha-synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies. (C) 2017 International Parkinson and Movement Disorder Society