Oxidative processes in neuronal systems

are markers of neurodegeneration in postmortem tissues. It is impossible to determine with certainty using postmortem analysis, whether oxidative stress has a primary role in neurodegeneration or is a secondary end-stage epiphenomenon. Growing evidence suggests that the generation of oxidants does not result simply from an accidental disruption of aerobic metabolism, but rather from an active process crucial for the nonspecific immune defenses of the brain. While essential for survival, these processes may be inappropriately activated to cause neurodegeneration. Neurons are highly susceptible to oxidative stress, which can induce both neuronal necrosis and apoptosis. Oxidants may also have more subtle roles in compromising the integrity of the bloodbrain barrier and in producing reactive changes in astrocytes that further propagate injury. Moreover, oxidative stress appears to provide a critical link between environmental factors, such as exposure to pesticides, herbicides, and heavy metals, and endogenous and genetic risk factors in the pathogenic mechanisms of neurodegeneration, particularly in Parkinson disease. Here, we discuss some recent insights into the diverse roles and controversies about the role of oxidants in neurodegeneration. A better understanding of the role of oxidants in neurodegeneration still holds a largely unfulfilled potential to reduce the burden of both acute and chronic neurodegeneration. Oxidative processes in neuronal systems Advances in understanding the chemical nature of oxidative attack on biological molecules have identified many new markers with which to examine postmortem tissues for evidence of oxidative injury. These markers include protein nitrotyrosine, carbonyls in proteins, fatty acid oxidation products, and oxidized DNA bases (1–6). Although biological oxidants have traditionally been viewed as highly reactive and destructive, they can be surprisingly selective and preferentially attack specific sites on macromolecules. For example, specific mAb’s raised to specific sequences from α-synuclein containing nitrotyrosine have revealed that nitrated α-synuclein selectively accumulates in Lewy bodies and protein inclusions in a wide range of pathologies (4) (Figure 1). Tyrosine nitration is one of the earliest markers found in Alzheimer disease brains, in the plaques of multiple sclerosis brains, and in degenerating upper and lower motor neurons in amyotrophic lateral sclerosis (ALS) patients (2, 5, 6). The association of specific oxidative damage with sites of injury in many different types of neurodegeneration suggests a common underlying mechanism. However, these markers could simply reflect secondary epiphenomena rather than having a causal role. A clear delineation of the causal connections cannot be given at present, but a growing body of evidence indicates that oxidants induce distinct pathological consequences that greatly amplify and propagate injury that leads to irreversible degeneration. When the generation of oxidants exceeds the rate at which endogenous antioxidant defenses can scavenge oxidants, proteins, lipids, DNA, and other macromolecules become targets for oxidative modification, which leads to deterioration of cellular structural architecture and signaling and ultimately death. Therefore, surviving neurons in human neurological disorders without evidence of biological oxidation could be the cells with the most effective antioxidant capacity. For example, neurons surviving in Huntington disease brains have strongly induced expression of the potent antioxidant enzyme mitochondrial manganese superoxide dismutase (Mn-SOD) (7). However, oxidative damage of biological targets does not necessarily translate to a pathogenic