Innate Immunity in ALS

Abstract

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is the most common form of motor neuron disease. It is a debilitating, late onset neurodegenerative disorder that is characterized by the progressive death of upper and ┙-motor neurons within the central nervous system (CNS) (Bruijn and Cleveland, 1996). This results in symptoms of muscle weakness and atrophy of skeletal muscles, leading to paralysis and eventual death due to failure of respiratory muscles (Cozzolino et al., 2008). ALS has a prevalence of approximately 1~2 per 100,000 worldwide with males being more susceptible than females (1.3 ~ 1.6: 1) (Strong, 2003, Woodruff et al., 2008b, Worms, 2001). The majority of ALS cases (~90%) are thought to be sporadic with unknown aetiology and no robust environmental risk factors, with the remaining 10% being familial ALS. Of this 10%, approximately 20% have been linked to dominant mis-sense point mutations in the Copper/Zinc superoxide dismutase 1 (SOD1) gene which results in a gain of unidentified deleterious properties (Rosen et al., 1993). The two aetiologies of ALS (i.e. sporadic and familial) are indistinguishable on the basis of their clinical and pathological features, including progressive muscle weakness, atrophy and spasticity, each of which reflects the degeneration and death of upper and ┙-motor neurons (Boillee et al., 2006). The mechanisms leading to ALS are still unclear but theories have suggested that glutamate excitoxicity, oxidative stress, protein aggregation, mitochondrial dysfunction, cytoskeletal abnormalities and neuro-inflammation may all play a role (Bruijn et al., 2004). The present chapter will review the role of innate immune system, in particular the complement system, during the disease progression of ALS. It will review evidence for an involvement of the innate immune Toll-like receptor (TLR) system and receptor for advanced glycosylation end products (RAGE) in ALS patients and animal models of ALS. It will also comprehensively evaluate the role of the innate immune complement cascade in this disease. Finally, the future therapeutic possibilities for ALS, aimed at targeting components of the innate immune system will be discussed. We provide compelling evidence for specific inhibitors of complement C5a receptors as novel treatment strategies for ALS.