Démêler l’altération du système endocannabinoïde dans la SLA : une nouvelle méthode thérapeutique axée sur la jonction neuromusculaire
Project Overview
A hallmark and the earliest event taking place in ALS is the denervation of neuromuscular junctions (NMJs), which results in muscle weakness and paralysis. Results from mentor’s lab and others demonstrated that NMJ denervation in ALS is a complex and dynamic process rather than just a manifestation of sudden global MN degeneration, characterized by an extensive and extended period of NMJ denervation-reinnervation cycles, months prior to the complete retraction of the MN axons in the slow progressing SOD1G37R mice. Furthermore, this disease is characterized by profound synaptic and glial alterations at the NMJ. As no cure yet exists, this disease is in desperate need of effective therapeutics for all cases. My previous studies identified endocannabinoid CB1 receptor (CB1R) as a key regulator of NMJ plasticity and repair, and its pharmacological or genetic blockade during nerve injury highlight great similarities to what was observed in ALS models. In ALS model, although some beneficial effect through the agonist use, the absence of motor benefit hindered eCB use. My preliminary results suggest that the loss of CB1R and increased eCB degradation enzyme, MAGL, levels at the NMJ of symptomatic SOD1G37R mice could explain the motor deficit observed in ALS. Thus, I hypothesize that by restoring eCB system at the NMJ via peripherally restricted pharmacology and glial specific-viral approach I will prevent or delay the onset of the disease improving NMJ and motor function and survival. Finally, I will study these changes in plasma and muscle biopsies as they could serve as new potential ALS biomarkers. The present proposal has the potential to highlight a new promising ALS therapeutic and biomarker target to explore.
Principal Investigator
Roberta Piovesana , Université de Montréal
Partners and Donors
ALS Society of Canada