Méthodes innovantes de transgénèse chez le rat : application pour la modélisation de la maladie de Parkinson

octobre 2017

Directeur(s) de thèse : Pr Clément Jimenez

Résumé de thèse

Recent advances in the transgenesis technique using the AAV approach have led to the generation of new animal models. In recent years, the development of models of Parkinson’s disease (PD) has improved understanding of the pathophysiological mechanisms of this degenerative pathology. However, no mammalian model recapitulates the required age-dependant parkinsonian degeneration, the α-synuclein inclusion pathology and motor and non-motor symptoms. The objective of my Ph.D work was to develop new transgenesis strategies in rats using these viral vectors for modeling PD. The challenge is to achieve a viral infection as early as possible in order to transduce as many dopaminergic neurons as possible. To this end, different strategies have been tested to improve transgenesis efficacy : i) injection in rete testis in young male to transduce germinal cells, ii) injection into early stage embryos, iii) in utero intracerebroventricular injection and iv) intracardiac injection in one day-old animals. Among them, in utero and intracardiac injections led to neuronal transgene expression in most regions of the brain.These techniques pave the way for the generation of new animal models of genetic diseases and offer unique opportunities for gene therapy.

Keywords : transgenesis, Parkinson’s disease, synuclein, adeno-associated virus, animal models.