Neurodegenerative diseases and oxidative stress

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Abstract
Oxidative stress has been implicated in the progression of a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis(ALS). These diseases are characterized by extensive oxidative damage to lipids, proteins and DNA. This damage can lead to cell death by a variety of different mechanisms, either by deactivating important processes or by upregulating toxic cascades. Oxidative stress is the result of an imbalance in the pro-oxidant/antioxidant homeostasis leading to the generation of toxic reactive oxygen species (ROS). ROS have a normal metabolic role in cell signalling and are generated by the interaction of oxygen with redox-active metal ions. As ROS can be damaging both metals and ROS are tightly regulated. Genetics has identified Aβ, α-synuclein and SOD as playing a pivotal role in AD, PD and ALS, respectively. These proteins are the major components of the deposits associated with these diseases. All these proteins have been shown to interact with redox-active metal ions with the subsequent generation of ROS. Aβ will coordinate copper and iron and generate H2O2 with the further generation of ROS through Fenton chemistry. α-synuclein regulates the uptake of vesicular dopamine, and a breakdown in this process allows the build-up of dopamine in the cytoplasm. Dopamine coordinates iron and induces the formation of ROS. Destabilization of the active site of SOD allows a corruption of this antioxidant enzyme such that it becomes pro-oxidant. Excitotoxicity is a downstream consequence of calcium dysregulation as a result of unregulated ROS. Drugs targeting this toxicity (Memantine in AD, Amantadine in PD and Riluzole in ALS) have modest clinical benefit. The antioxidant α-tocopherol has shown clinical promise against AD. Inhibiting metal-mediated redox processes has shown benefit in mouse models of AD and PD and encouraging promise in a small Phase II clinical trial for AD.