Étude des déficits mitochondriaux et comportementaux sociaux liés à l'autisme : inactivation du gène MFN2 chez le poisson-zèbre et restauration par les gènes MFN2 humains
DOI :
https://doi.org/10.18192/osurj.v5i2.7938Résumé
Le trouble du spectre de l’autisme (TSA) est une condition neurodéveloppementale complexe définie par l’interaction sociale affaiblie et des comportements répétitifs (1). Des données émergentes suggèrent qu'un dysfonctionnement mitochondrial pourrait contribuer aux TSA. Une production d'énergie neuronale adéquate est essentielle au bon fonctionnement des synapses, ce qui favorise les comportements prosociaux. La mitofusine-2 (MFN2), un régulateur clé de la fusion mitochondriale, présente une expression réduite chez les patients atteints de TSA et est associée à une morphologie mitochondriale anormale qui altère la production d'ATP. Cependant, le lien de causalité direct entre le dysfonctionnement mitochondrial induit par MFN2 et les comportements sociaux liés à l'autisme reste incertain (2).
Cette étude examine les effets de l’inactivation de la MFN2 sur l’énergie neuronale et le comportement social chez le poisson-zèbre (Danio rerio) et si l'expression de la MFN2 humaine peut remédier à ces déficits. Le poisson-zèbre est largement utilisé comme modèle de développement neurologique car il possède des voies génétiques conservées liées aux troubles neurologiques humains et présente des comportements sociaux quantifiables tels que le regroupement en bancs. De plus, la transparence de leurs embryons et leur développement rapide permettent une manipulation génétique efficace et l'observation en temps réel des effets sur le développement. Les embryons de poisson-zèbre seront divisés en quatre groupes : de type sauvage, ayant reçu une injection simulée, présentant une inactivation de la MFN2 et un groupe présentant une inactivation recevant de l’ARNm MFN2 humain. L'inhibition de la MFN2 sera réalisée par injection de morpholino antisens au stade unicellulaire, les niveaux d'expression étant validés par réaction en chaîne par polymérase quantitative et par un test Western Blot. Pour évaluer l'impact sur l'énergie cellulaire et la sociabilité, les niveaux d'ATP neuronal seront mesurés par un test de luminescence, tandis que la cohésion sociale sera évaluée par un test comportemental de regroupement avec un logiciel de suivi automatisé. La distance interindividuelle moyenne sera quantifiée comme principal indicateur de la cohésion du groupe.
L'hypothèse est que l'inhibition de la MFN2 altère la fusion mitochondriale, entraînant une diminution de la disponibilité d'ATP neuronal et une perturbation des comportements prosociaux, tandis que l'expression de la MFN2 humaine rétablit la production d'énergie et le regroupement en bancs. En établissant la MFN2 comme un lien essentiel entre la dynamique mitochondriale et la sociabilité, cette recherche permettra de mieux comprendre le rôle des dysfonctionnements métaboliques dans les TSA, et d'identifier des voies moléculaires potentielles pour des interventions thérapeutiques.
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