Protective potential of the X protein in DOA (DOAX)

P.I. Pascale Belenguer

The impact of visual handicaps has risen in our developed countries with the contemporary means of visual communication and population ageing. Optic nerve atrophies are often due to defects in mitochondria, as Dominant Optic Atrophy (DOA) caused by mutations of the mitochondrial OPA1 protein, a large GTPase involved in mitochondrial dynamics. As there is no cure for DOA, we explore an original therapeutic avenue, inspired by the tendency of viruses to block apoptosis. We focus on a virus-encoded protein called X, demonstrated by our collaborator D. Dunia’s team to protect neurons against diverse neurodegenerative insults. Interestingly, these effects require the localization of X in mitochondria and are correlated to modification of mitochondrial dynamics. We thus test whether X can protect neurons against the consequences of OPA1 deficiencies using both in vitro and in vivo models.

Collaborators :  Daniel Dunia (CPTP, Purpan, Toulouse), Bernd Wissinger (University of Tubingen, Germany)

Publications :

• Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Arnauné-Pelloquin L, Davezac N, Mils V, Miquel MC, Rojo M, Belenguer P. (2016). Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity Neurobiol Dis. 90, 3-19.
• Bertholet A.M., Millet A., Guillermin O., Daloyau M., Davezac N., Miquel MC. & Belenguer P. (2013) OPA1 loss of function affects in vitro neuronal maturation BRAIN;136(Pt 5):1518-33.
• Ferré CA, Davezac N, Thouard A, Peyrin JM, Belenguer P, Miquel MC, Gonzalez-Dunia D, Szelechowski M. (2016) Manipulation of the N-terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential FASEB J. FASEB J, 30, 1523-1533.
• Szelechowski M, Bétourné A, Monnet Y, Ferré CA, Thouard A, Foret C, Peyrin JM, Hunot S, Gonzalez-Dunia D. (2014) A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson's disease. Nat Commun. 2014, 21;5:5181.

Funding