The role of free radicals in the aging brain and Parkinson's Disease: convergence and parallelism

Abstract

Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson's disease (PD). There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Dopaminergic neurons show linear fallout of 5-10% per decade with aging; however, the rate and intensity of neuronal loss in patients with PD is more marked than that of aging. Here, we enumerate the common link between aging and PD at the cellular level with special reference to oxidative damage caused by free radicals. Oxidative damage includes mitochondrial dysfunction, dopamine auto-oxidation, α-synuclein aggregation, glial cell activation, alterations in calcium signaling, and excess free iron. Moreover, neurons encounter more oxidative stress as a counteracting mechanism with advancing age does not function properly. Alterations in transcriptional activity of various pathways, including nuclear factor erythroid 2-related factor 2, glycogen synthase kinase 3β, mitogen activated protein kinase, nuclear factor kappa B, and reduced activity of superoxide dismutase, catalase and glutathione with aging might be correlated with the increased incidence of PD.

Keywords: Parkinson’s disease; aging; free radicals; mitochondrial dysfunction; nrf2; α-synuclein.

Figure 1

Schematic representation of the action of free radicals on biological molecules such as lipids, proteins, and DNA. Free radicals react largely in a nonspecific manner with nucleic acids, proteins, and membrane lipids and cause cell injury through various mechanisms as shown. Details are discussed in the main text.

Figure 2

Generation of free radicals in aging and Parkinson’s disease (PD). A major source of free radicals is mitochondria (mt), mitochondrial complex inhibition either by toxins or aging hampers the mitochondrial respiratory chain, which causes incomplete oxygen reduction, thereby generate reactive species including deleterious superoxide anion (O₂⁻) which is converted to hydrogen peroxide (H₂O₂) and then finally to hydroxyl radical (·OH) through the Fenton reaction which involves Fe²⁺ or Cu²⁺ (not shown). ·OH is a potent inducer of membrane lipid peroxidation. Oxyradicals can also be generated in response to calcium influx. Nitric oxide (NO) interacts with O₂⁻ to form peroxynitrite (NO₃⁻)_, Reactive oxygen species (ROS) and reactive nitrogen species (RNS) contribute to oxidative and nitrosative stress, respectively, which finally causes neurodegeneration. Mitochondrial activity is lost or mitochondrial DNA is damaged during aging, which could lead to generation of ROS. Cytoprotective pathways are activated with the generation of free radicals. Activation of the Nrf2 pathway provides protection by regulating redox balance, whereas the NF-κB pathway causes increased cytokine release which is included in positive feedback to initiate the inflammatory cascade and also through influx of calcium ions inside the extracellular space.