Lakhdar, L. | bioRxiv Science

bioRxiv2018

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

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.

neuroscience↗

bioRxiv2017

Bank Vole Immunoheterogeneity May Limit Nephropatia Epidemica Emergence In A French Non-Endemic Region

Ecoevolutionary processes affecting hosts, vectors and pathogens are important drivers of zoonotic disease emergence. In this study, we focused on nephropathia epidemica (NE), which is caused by Puumala hantavirus (PUUV) whose natural reservoir is the bank vole, Myodes glareolus. Despite the continuous distribution of the reservoir in Europe, PUUV occurence is highly fragmented. We questioned the possibility of NE emergence in a French region that is considered to be NE-free but that is adjacent to a NE-endemic region. We first confirmed the epidemiology of these two regions using serological and virological surveys. We used bank vole population genetics to demonstrate the absence of spatial barriers that could have limited dispersal, and consequently, the spread of PUUV into the NE-free region. We next tested whether regional immunoheterogeneity could impact PUUV chances to establish, circulate and persist in the NE-free region. Immune responsiveness was phenotyped both in the wild and during experimental infections, using serological, virological and immune related gene expression assays. We showed that bank voles from the NE-free region were sensitive to experimental PUUV infection. We observed high levels of immunoheterogeneity between individuals and also between regions. In natural populations, antiviral gene expression (Tnf and Mx2 genes) reached higher levels in bank voles from the NE-free region. During experimental infections, anti-PUUV antibody production was higher in bank voles from the NE endemic region. Altogether, our results indicated a lower susceptibility to PUUV for bank voles from this NE-free region, what might limit PUUV circulation and persistence, and in turn, the risk of NE.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC=\"FIGDIR/small/130252_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (25K):\norg.highwire.dtl.DTLVardef@f90a69org.highwire.dtl.DTLVardef@1a9e0dorg.highwire.dtl.DTLVardef@17e96b8org.highwire.dtl.DTLVardef@1d936e8_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗