Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease that leads to degeneration of motor neurons in the cortex, brainstem and spinal cord resulting in progressive paralysis and ultimately death. The occurrence of ALS is largely sporadic (SALS), however approximately five to ten percent of cases are familial, associated with mutations in one of several genes including Cu,Zn SOD-1, Alsin, Senataxin, TDP-43 and FUS/TLS. There is currently no prophylactic therapy or cure for ALS and the only approved treatment, riluzole, extends survival only a few months and is considered ineffective. Given the lack of effective therapies and the estimated lifetime risk of developing SALS ranging from 1 in 400 to 1 in 1000, the need for disease biomarkers and disease-modifying therapies is critical. Neuroinflammation has received attention as a mechanism that participates in motor neuron loss in ALS, due in large part to the recognition of immune-mediated contributions to other neurodegenerative diseases, including multiple sclerosis, Alzheimer's and Parkinson's disease. The complement system, a major arm of the innate immune system, drives neuroinflammation along with other inflammatory mediators in most, if not all, central nervous system diseases and infections. There is growing evidence that complement contributes to neurodegeneration in ALS. Several studies have found evidence of complement activation and deposition in the spinal cord of ALS patients as well as elevated levels of complement activation fragments in cerebrospinal fluid (CSF) or serum. In addition, rodent models of ALS, have shown changes in complement gene expression and complement deposition in motor neurons and neuromuscular junctions in pre- and symptomatic stages of murine ALS. Nevertheless, the role of complement in the development and progression of ALS remains ill-defined. We have taken a systematic approach to address the role of complement in murine ALS by crossing SOD1G93A transgenic mice with mice deficient in C3 or C5, the two central proteins of the complement system. We observed a time-dependent deposition of C9 in the spinal cords of SOD1G93A mice suggesting that the membrane attack complex contributes to neurodegeneration in ALS. Furthermore, we found that female C5+/- x SOD1G93A mice survived significantly longer than the respective genders in SOD1G93A mice, an observation that correlates with the reduced C5 levels in female mice. We hypothesize that C5 plays a central role in the development and progression of ALS and will address this hypothesis by comparing the clinical and histological ALS phenotypes of both genders of mice that are SOD1G93A tg and deficient in C3, C5, C5aR or C9 to SOD1G93A mice. These studies will provide new information regarding the role of complement in ALS and potentially new therapeutic directions.
Neuroinflammation has received attention as a mechanism that participates in motor neuron loss in ALS, in part due to the recognition of immune-mediated contributions to other neurodegenerative diseases, including MS, AD and PD. The complement system, a major arm of the innate immune system, drives neuroinflammation in many CNS diseases and infections. There is growing evidence that complement contributes to neurodegeneration in ALS.
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