Analysis of the molecular and cellular mechanisms underlying the neuroprotective properties of a virus-derived protein – MitoX

As obligatory parasites, viruses have refined diverse strategies aimed at manipulating the host cell physiology for their own benefit. For example, it has been shown that the non-cytolytic persistence of Bornavirus in infected neurons was favored by the expression of a small non-structural 10 kDa viral protein called X. This protein localizes preferentially in the mitochondria during infection, where it blocks several host cell defense mechanisms, notably apoptosis. Strikingly, we recently demonstrated that the singled-out expression of X could also protect neurons against neurodegeneration, both in vitro and in a mouse model of Parkinson's disease, even when expressed independently from the viral context.

Even if the neuroprotective promise of the X protein is now well established, knowledge about the underlying mechanisms is still scarce. A better understanding of the mechanisms of action of the X protein may thus improve its therapeutic potential, while providing further insight on its biology and impact on mitochondrial physiology. Moreover, it is of the utmost importance to confirm its neuroprotective effects using more chronic neurodegenerative models than those used in the initial proof of concept studies, and that would strongly implicate mitochondrial dysfunction.

In this collaborative research proposal, we will gather complementary expertise from the two participating teams to decipher the impact of the X protein on mitochondria biology. More specifically, we propose:

- To unravel the impact of the X protein on mitochondrial parameters, including respiration or ATP production. Moreover, we will pursue and expand our initial studies suggesting that the X protein has a strong impact on mitochondrial dynamics (which refers to the continuous processes of fission and fusion of this organelle) by assessing this phenomenon in real time using live-cell imaging approaches;

- To determine the cellular partners of the X protein in mitochondria and to test their implication in neuroprotection;

- To evaluate the neuroprotective potential of the X protein, or X-derived peptides, using an ongoing and chronic neurodegenerative model preferably centered on mitochondrial dynamics. To this aim, we will use models for type 1 dominant optic atrophy, which have been closely linked to impairment of mitochondrial dynamics resulting from mutations in the OPA1 protein.

All required tools and research plan are already in place, resulting from the complementarities of expertise between the two participating scientific teams. Moreover, our project is backed up by convincing and solid preliminary data. We hope thereby to gain important insight on the neuroprotective mechanisms used by the X protein, notably through a better definition of its cellular binding partners and affected signaling pathways. In addition, our endeavor is also to further validate the therapeutic promise of this viral protein, using a model of optic pathology closely linked to impaired mitochondrial dynamics.