Abstract
Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases characterized by inclusions mainly composed of α-synuclein (α-syn) aggregates. The objective of this study was to investigate if β-synuclein (β-syn) overexpression could have beneficial effects by inhibiting the aggregation of α-syn. The M83 transgenic mouse is a model of synucleinopathy, which develops severe motor symptoms associated with aggregation of α-syn. M83 neonate or adult mice were injected with adeno-associated virus vectors carrying the human β-syn gene (AAVβ-syn) or green fluorescent protein gene (AAVGFP) using different injection sites. The M83 disease was - or not - accelerated using extracts of M83 brains injected with brain extract from mouse (M83) or human (MSA) origins. AAV vectors expression was confirmed using Western blot and ELISA technics. AAV mediated β-syn overexpression did not delay the disease onset or reduce the α-syn phosphorylated at serine 129 levels detected by ELISA, regardless of the AAV injection route and the inoculation of brain extracts. Instead, a proteinase-K resistant β-syn staining was detected by immunohistochemistry, specifically in sick M83 mice overexpressing β-syn after inoculation of AAVβ-syn. This study indicated for the first time that viral vector-mediated β-syn overexpression could form aggregates in a model of synucleinopathy.
Highlights
Accelerated using extracts of M83 brains injected with brain extract from mouse (M83) or human (MSA)
Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are synucleinopathies, characterized by inclusions mainly composed of an aggregated form of α-synuclein (α-syn) in the central nervous system (CNS)
According to in vitro studies, unlike α-syn, β-syn alone is not able to form aggregates, but could instead interact with α-syn and reduce its capacity to aggregate[6]. These anti-aggregative features have been investigated in vivo, and some of these studies reported a neuroprotective effect and reduction of α-syn inclusions after overexpression of the human β-syn mediated by DNA microinjection or lentiviral vectors in the transgenic D mouse model, overexpressing human wild-type α-syn[7,8]
Summary
Accelerated using extracts of M83 brains injected with brain extract from mouse (M83) or human (MSA). As for prions, aggregated forms of α-syn propagate within the CNS during the associated neuro-degenerative diseases This characteristic was initially suggested in humans by Braak’s description of PD stages, and was confirmed later in experimental models of synucleinopathies, in particular in the M83 transgenic mouse model[1]. M83 mice, disease onset can be accelerated by the intracerebral inoculation of brain homogenates from sick M83 mice[2] This model was further characterized by development of an original ELISA that detects, and allows to quantify, the pathological α-syn in sick M83 mice[3,4,5]. Two recent studies by Taschenberger et al and Landeck et al
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