Presynaptic degeneration in ALS mouse neuromuscular junctions and a targeted therapeutic approach

项目总结/文摘:

Project Summary/Abstract: Amyotrophic Lateral Sclerosis (ALS) in a neurodegenerative disease that results in the progressive deterioration and loss of function of the motor neurons leading to paralysis. Studies indicated that synaptic transmission at neuromuscular junctions (NMJs) is reduced in early stages of the disease NMJ denervation occurs while neuronal cell bodies in the spinal cord remain intact. This observation in which NMJ dysfunction precedes motor neuron death suggests ALS is a “dying-back” neuropathy. The etiology of ALS is currently unknown, and no effective treatment exists for ALS to improve neuromuscular transmission, which would improve quality of life for ALS patients by increasing neuromuscular strength and may prolong lifespan. Therefore, my long-term goal is to identify a new intervention method to improve neuromuscular function by reducing dying-back neuropathy in ALS. Our strategy is to test a novel Cav2-specific voltage-gated calcium channel gating modifier that we have developed (GV-58), a pharmacological intervention that enhances the activation of the neuromuscular system. GV-58 is innovative because it is based on a target that has not been tested previously for ALS, namely, strengthening synaptic transmission to maintain NMJ innervation. Here, we propose to characterize neuromuscular weakness at different stages of disease progression in SOD1G93A ALS model mice and test the effects of GV-58 both acutely and after daily chronic administration. This is to determine if GV-58 can play a role in delaying disease onset or in recovery of NMJ strength and whether that can lead to improved SOD1G93A mouse survival.