Environmental and Genetic Contributions in an ALS Animal Model

ALS is an adult onset neurodegenerative disease characterized by spreading paralysis. The disease is poorly understood, leading to no effective therapeutics and an average survival time of only five years. While an underlying genetic factor has been identified in a small subset of familial patients (10-15%), the vast majority of patients are sporadic. This suggests a complicated genetic risk mosaic in that there maybe numerous mutations that lead to an increase risk of disease. Given the wide variations in genetic risks and variable clinical presentations with the same genetic predispositions, environmental contributions are also very important. Veterans and athletes have been shown to be at an increased risk of developing the disease, suggesting a potential role for injury. Here we explored the relative contributions of genetics and environment using a rat model to combine genetic (SOD1G93A rats) and environmental (sciatic nerve crush) factors. We showed that nerve injury led to increased central nervous system inflammation accompanied by faster disease onset and decreased survival. This was likely due to increased mutant protein aggregation and synaptic loss which was observed in the areas shown to be affected by increased inflammation. While the exact signaling pathways involved in this increased inflammation are unknown, one potential target is neuregulin. Neuregulin (NRG) is a growth factor expressed by neurons which binds to receptors on glial cells. NRG was shown here to increase expression of pro-inflammatory cytokines such as TNF-alpha and Nox2, and conditioned media from high dose NRG treated microglia is toxic to motor neurons. Also at high doses, NRG induced expression of Cx3Cr1, a component of the fractalkine system that plays a role in synaptic modulation. It was also shown here that injury caused C1q tagging of synapses on injured neurons, a component of the complement system and also known to be active in synaptic strippping in neurodegenerative disease such as Alzheimer’s. Taken together, this thesis work presents a new model that that combined a genetic susceptibility with environmental injury, leading to increased NRG signaling and toxic protein aggregation which then over-activates pro-inflammatory microglia and causes complement-mediated synaptic stripping and neuronal death. While much additional research is needed, targeting this pathway could prevent pathological inflammation and prevent disease spread.