Project Overview
Study of perisynaptic Schwann cells contribution on NMJ reinnervation efficiency in ALS
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motoneurons loss and leading to death within 5 years after diagnosis. Changes in the neuromuscular junctions (NMJs) constitute one of the hallmarks of ALS pathophysiology occurring prior to symptoms in humans and animal models, making them critical therapeutic targets. In physiological conditions, NMJ synaptic functions, maintenance, and repair are regulated by perisynaptic Schwann cells (PSCs).
However, in the context of ALS disease, PSCs functions are maladapted due to hyper muscarinic activity preventing them to regulate NMJ repair. In addition, NMJs exhibit an abnormal dynamism marked by denervation-reinnervation cycles. We hypothesize that the maladaptive behaviour of PSCs prevents reinnervating NMJs from regaining full functionality in ALS leading to the unstable NMJs that are prone to denervation.
To this end, we developed a novel in-vivo approach to study reinnervation and allowing us to lesion a few axons and denervate NMJs downstream. After a recovery phase of 5 to 28 days, muscles and nerves are dissected, and electrophysiological recordings are performed to compare the function of the reinnervated NMJs with their non-injured control neighbours. Post-hoc immunolabeling and confocal imaging is then conducted to assess innervation integrity. Our results show that the synaptic profile of ALS NMJs is similar to recently reinnervated NMJs, indicative of the physiological immaturity of NMJs in ALS. Moreover, in ALS SOD1 NMJs, the experimental cycle of denervation-reinnervation seems to worsen this immature synaptic profile. We also noticed that PSCs signs of repair are more disorganized in SOD1 animals. The roles of PSCs will be examined by restoring their muscarinic excitability via an AAV-directed targeting while correlating the results based on our previous readout. In conclusion, we aim to show that understanding this denervation-reinnervation phase offers a new avenue for promoting NMJ survival and tailoring ALS therapies.
Partners & Donors
ALS Society of Canada
