Neuroprotective properties of peptides derived from the Bornavirus X protein – X-protect

Control of cellular apoptosis is a strategy often used by viruses to limit cellular damage. For neurotropic viruses, it is one key element that allows them to persist in the brain and to cope with the limited capacity of renewal of neurons. To achieve this goal, many viruses express proteins able to limit or prevent cell death. This has led to the tantalizing hypothesis that some of these proteins may serve as neuroprotective tools for the treatment of various neurodegenerative disorders, which are characterized by a progressive neuronal impairment and demise.
In this proposal, our goal is to test whether polypeptides derived from the X protein of Bornavirus can be used to promote neuronal survival and protect against axonal degeneration. We recently demonstrated that the Bornavirus X protein has a clear neuroprotective effect in vitro, by acting at the mitochondrial level. This protection was also observed in vivo, in a mouse model of Parkinson’s disease (PD) consecutive to intoxication with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl), a dopaminergic neurotoxin and mitochondrial poison. Interestingly, evidence suggests that the preferential death of dopaminergic neurons of the nigro-striatal pathway in PD may be related to mitochondrial dysfunction and especially to complex I respiratory chain impairment. We have also recently characterized one cellular partner for the X protein. In parallel, we have designed overlapping peptides covering the whole sequence of X. Among these peptides, one appears to display in vitro neuroprotective properties comparable to that seem with the full-length protein.
The proposed project, which will build on these recent and encouraging results, aims at further validating the proof on concept of the neuroprotective promise of X-derived peptides in vivo. More specifically, we propose:
1) To test the neuroprotective properties of a recently identified cell-permeable peptide derived from Bornavirus X protein in the MPTP mouse model of PD, after intracerebral administration and at different stages of the neurodegenerative process.
2) To assess whether protection against neurodegeneration can also be observed if this peptide is administered through the systemic route, either intravenously or intraperitoneally.
3) Based on our recent results, to refine this therapeutic peptide by determining the minimal motif derived from X that is responsible for protection.
All required tools and research plan are already in place, resulting from the complementarities of expertise between the two participating scientific teams. The final goal of this proposal is to patent the most promising peptides through our collaboration with the technology transfer team and to pursue the validation of their therapeutic potential in other relevant animal or cellular models.