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bioRxiv · 10.1101/300822

Investigating the neuroprotective effect of AAV-mediated β-synuclein overexpression in a transgenic model of synucleinopathy

Sargent, D.·Betemps, D.·Drouyer, M.·Verchere, J.·Gaillard, D.·Arsac, J.-N.·Lakhdar, L.·Salvetti, A.·Baron, T.
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Abstract

Parkinsons disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases characterized by inclusions mainly composed of -synuclein (-syn) aggregates. The objective of this study was to investigate if {beta}-synuclein ({beta}-syn) overexpression could have beneficial effects by inhibiting the aggregation of -syn. The M83 transgenic mouse is a model of synucleinopathy, which develops severe motor symptoms associated with aggregation of -syn. M83 neonate or adult mice were injected with adeno-associated virus vectors carrying the human {beta}-syn gene (AAV{beta}-syn) or green fluorescent protein gene (AAVGFP) using different injection sites. One or two months later, M83 disease was accelerated or not using brain M83 extracts from mouse (M83) or human (MSA) origins. AAV mediated {beta}-syn overexpression detected by ELISA did not delay the disease onset, regardless of the AAV injection route and of the inoculation of brain extracts. Accordingly, phosphorylated -syn levels detected by ELISA in sick mice were similar after injecting AAV{beta}-syn or AAVGFP. Instead, immunohistochemistry analysis of {beta}-syn indicated the presence of proteinase-K resistant {beta}-syn staining specifically in sick M83 mice inoculated with AAV{beta}-syn. This study indicated for the first time that {beta}-syn could form aggregates in a model of synucleinopathy when it is expressed by a viral vector.

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Sargent, D., Betemps, D., Drouyer, M., Verchere, J., Gaillard, D., Arsac, J.-N., Lakhdar, L., Salvetti, A., Baron, T.. 2018-04-14. Investigating the neuroprotective effect of AAV-mediated β-synuclein overexpression in a transgenic model of synucleinopathy. https://doi.org/10.1101/300822

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