Objective: We aimed to develop AAV-based models of MSA

Background: Multiple system atrophy (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 (α-syn) forming cytoplasmic inclusions in oligodendrocytes. Adeno-associated viruses (AAV) allow efficient targeting of disease-associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of α-syn in the substantia nigra in the context of Parkinson’s disease.

Methods: Chimeric AAV1/2 vectors expressing either human wild-type α-syn or the green fluorescent protein under the control of the mouse myelin basic protein were injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor assessment prior to histopathological analysis at 3 and 6 months.

Results: Injection of AAV expressing α-syn 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-syn accumulation, including phosphorylated and proteinase-K resistant α-syn was detected in the striatum and substantia nigra.

Conclusions: AAV-mediated oligodendroglial expression of α-syn allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how α-syn accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for the pre-clinical validation of therapeutic strategies

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MDS Abstracts - https://www.mdsabstracts.org/abstract/viral-mediated-oligodendroglial-alpha-synuclein-expression-models-multiple-system-atrophy/