Time to get personal: A framework for personalized targeting of oxidative stress in neurotoxicity and neurodegenerative disease

The annual cost for neurological disorders in the United States was $789 billion in 2014, and with an aging population these numbers are expected to significantly increase in the next 50 years. Neurodegenerative diseases make up a significant portion of these costs. Neurodegenerative diseases are characterized by the loss of neuronal populations in specific regions of the brain. Although the cause is still unknown for most of these diseases, both genetic and environmental factors are thought to play important roles. There are multiple convergent mechanisms underlying the unique susceptibility of neurons to degeneration, including aging, inflammation, mitochondrial dysfunction, and oxidative stress. Oxidative stress (OS) is of particular importance because evidence indicates that the neuronal populations lost in neurodegenerative diseases are particular susceptible to OS. OS is a complex neurotoxic mechanism that arises from excessive generation of free radicals such as reactive oxygen species (ROS), reduction in anti-oxidant factors, or a combination of the two. A complex interplay between the endogenous susceptibility of the brain, genetic factors, and environmental exposures leads to the harmful generation of OS in the brain and contributes significantly to the initiation and/or progression of neurodegeneration. Unfortunately, therapeutics for neurodegenerative diseases have consistently failed in clinical trials. Thus, a better understanding of the interplay between genetic susceptibility and common molecular mechanisms of environmental contributors to OS generation could aid in elucidation of novel therapeutic strategies for neurodegenerative diseases. This review will explore the current picture of oxidative stress in the brain as it relates to neurotoxicity, specifically exploring common mechanisms behind the endogenous susceptibility of the brain to OS, genetic susceptibility and environmental exposures leading to neurotoxicity, to identify precision/personalized medicine approaches for improving therapeutic outcome.