Reactive oxygen and nitrogen species - A driving force in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressive neurodegenerative disease. Multiple pathogenic mechanisms contribute to motoneuron injury in ALS that involve the following: (1) misfolded proteins; (2) mitochondrial dysfunction; (3) neurofilament/cytoskeletal alterations; (4) mRNA mishandling from mRNA processing to translation; (5) endoplasmic reticulum (ER) and Golgi dysfunction including ER stress, the unfolded protein response (UPR), and protein degradation malfunction; (6) neuroinflammation with subsequent oxidative injury and neurotoxicity; and (7) astroglial alterations. However, the initiating pathogenic mechanism and the ensuing pathogenic processes responsible for spreading the disease from the original site of initiation are not clearly delineated. Reactive oxygen and nitrogen species (RONS) play significant roles exacerbating disease in ALS by aggravating all of the pathogenic mechanisms that induce motoneuron injury. The reactive species include nitric oxide (NO), superoxide (O₂ ^•-), hydrogen peroxide (H₂O₂), and peroxynitrite. One of, if not the main source of RONS in the CNS in ALS, is microglia. Microglia are activated at the onset of disease and become increasingly activated with disease progression, generating escalating levels of O₂ ^•- from NADPH oxidase and NO by iNOS. Excess O₂ ^•- is also generated in motoneurons from mitochondrial respiration, and NO is generated by motoneurons and astroglia with disease progression. The NO rapidly reacts with O₂ ^•- to form peroxynitrite, a highly toxic RONS which modifies DNA, proteins, and lipids. In this chapter, the proposed mechanisms of motoneuron injury will each be discussed based on what occurs in patients and animal models, including a discussion on the roles RONS play in aggravating the pathologies.