Lifespan Of SOD1 Mice Research Articles

Semaphorin 3A signaling through neuropilin-1 is an early trigger for distal axonopathy in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive distal axonopathy that precedes actual motor neuron death. Triggers for neuromuscular junction degeneration remain to be determined, but the axon repulsion factor semaphorin 3A (Sema3A), which is derived from terminal Schwann cells, is a plausible candidate. This study examines the hypothesis that Sema3A signaling through its motor neuron neuropilin-1 (NRP1) receptor triggers distal axonopathy and muscle denervation in the SOD1G93A mouse model of ALS. Neuropilin-1 was found to be expressed in axonal terminals at the mouse neuromuscular junction in vivo and in NSC-34 motor neuron–like cells in vitro. In differentiated NSC-34 cells, an anti-NRP1A antibody that selectively blocks Sema3A binding to NRP1 prevented Sema3A-induced growth cone collapse. Furthermore, intraperitoneal injections of anti-NRP1A antibody administered twice weekly from age 40 days significantly delayed and even temporarily reversed motor functional decline while prolonging the life span of SOD1G93A mice. Histologic evaluation at 90 and 125 days revealed that anti-NRP1A antibody reduced neuromuscular junction denervation and attenuated pathologic alterations in ventral roots at late-stage disease. These data suggest that peripheral NRP1A signaling is involved in the pathobiology of this ALS model and that antagonizing Sema3A/NRP1 binding or downstream signals could have implications for the treatment of ALS.

420. Hydrodynamic Limb Vein Delivery of Naked IGF-1 Plasmid DNA Provides Therapeutic Benefit in SOD1(G93A) Murine ALS Model

Motor neuron degeneration and death in ALS can be mitigated by neurotrophic factors. A number of neurotrophic factors (e.g., VEGF, GDNF and IGF-1) have been demonstrated to promote survival and regeneration of motor neurons both in vitro and in vivo. An increase in the lifespan of SOD1 mice was observed following delivery of viral vectors expressing GDNF or IGF-1. For human gene therapy, a non-viral approach would be preferred. Recently, highly effective transfer of plasmid DNA expression vector to skeletal muscle was described using hydrodynamic delivery of pDNA solutions into limb veins. This method promises a safe non-viral gene therapy route that is equally effective in small and large research animals.