Venue: Salle de conférence Neurocentre Magendie
Defense in french
Jeflie Tournezy
Team: Oliet, Neurocentre Magendie
Thesis supervisor: Stéphane Chevallier
Title
Therapeutic effects of the Borna virus X protein in SOD1G93A mice
Abstrac
Today, Amyotrophic Lateral Sclerosis (ALS) remains an incurable disease for which therapeutic trials have been unsuccessful. It is therefore essential to propose new therapeutic approaches that would slow the progression of the disease and prolong patient survival.
Among the pathophysiological characteristics described, mitochondrial dysfunctions are one of the earliest events and could be the origin of the progressive loss of motor neurons. Restoring mitochondrial functions could therefore constitute a therapeutic area of interest to develop new therapies against this disease.
With this in mind, we were interested in the X protein of the Bornavirus (BDV for Borna Disease Virus). When it targets mitochondria, the X protein inhibits the apoptosis of neurons and protects them from degeneration in an animal model of Parkinson’s disease (Szelechowski et al., 2014). This neuroprotective action of the X protein resides in its last 29 carboxy-terminal amino acids which constitute the PX3 peptide. In addition, a modification to increase the mitochondrial localization of the protein X (XA4 protein) has shown improved neuroprotective effects in vitro.
This thesis aimed to propose a new preclinical therapeutic approach, consisting in protecting motor neurons by using the neuroprotective properties of the Bornavirus X protein.
First, we tested the neuroprotective effects of the X protein and its derived peptide PX3 in a well-characterized model of ALS, the SOD1G93A mice. Administration of the PX3 intranasally and the X intramuscularly via a viral vector (CAV2-X) slowed the progression of the disease and increased the survival of lumbar motor neurons. However, this treatment did not increase the life expectancy of the mice.
Then, we used adeno-associated viruses (AAV) as gene transfer tools. More specifically, we used AAV serotype 10 (AAV10) to administer the gene encoding the X protein (AAV10-X) or its modified form, the XA4 protein (AAV10-XA4) to SOD1G93A mice. We evaluated the effects of these treatments on motor performances, life span, denervation of the neuromuscular junction, and preservation of lumbar and phrenic motor neurons (motor neurons innervating the diaphragm).
Our results show that the X and XA4 proteins slowed the degeneration of lumbar motor neurons. Furthermore, while the X protein delayed the onset of motor deficits, the XA4 protein extended the life expectancy of the animals. The maintenance of motor performances in mice treated with X protein was associated with better preservation of the neuromuscular junction compared to untreated SOD1G93A mice.
In addition, the administration of X or XA4 proteins to SOD1G93A mice blocks the degeneration of phrenic motor neurons, allowing them to return to values like the wild-type group.
Although further investigations are needed to better understand the mechanisms involved in the effects of these proteins, our work demonstrates their certain therapeutic effects, on the extension of the life span, on the preservation of the neuromuscular junction, and the limitation of the degeneration of the spinal motor neurons. These studies open a new therapeutic avenue against ALS.
Key words: amyotrophic lateral sclerosis; SOD1G93A mice; motor neuron degeneration; motor tests; life span
Jury
M. RAOUL, Cédric – Directeur de recherche-Université de Montpellier – INSERM U1051 – rapporteur
Mme BERTRAND, Sandrine – Directrice de recherche-Université de BORDEAUX – examinatrice
M. GOIZET, Cyril – Praticien hospitalier – Bordeaux- examinateur
Mme CHEVALLIER, Stéphanie – Maitre de conférences – Université Bordeaux – directrice de thèse
M. LE MASSON Gwendal Professeur-Praticien hospitalier-Bordeaux-membre invité
Membres invités :
Mme DA CRUZ, Sandrine-Directrice de recherche- Leuven Brain Institute Belgique-examinatrice
M. ROBITAILLE, Richard-Directeur de recherche-Université de Montréal- rapporteur