Abstract
Neurological function deficits due to cerebral ischemia or neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have long been considered a thorny issue in clinical treatment. Recovery after neurologic impairment is fairly limited, which poses a major threat to health and quality of life. Accumulating evidences support that ROS and autophagy are both implicated in the onset and development of neurological disorders. Notably, oxidative stress triggered by excess of ROS not only puts the brain in a vulnerable state but also enhances the virulence of other pathogenic factors, just like mitochondrial dysfunction, which is described as the culprit of nerve cell damage. Nevertheless, autophagy is proposed as a subtle cellular defense mode against destructive stimulus by timely removal of damaged and cytotoxic substance. Emerging evidence suggests that the interplay of ROS and autophagy may establish a determinant role in the modulation of neuronal homeostasis. However, the underlying regulatory mechanisms are still largely unexplored. This review sets out to afford an overview of the crosstalk between ROS and autophagy and discusses relevant molecular mechanisms in cerebral ischemia, AD, and PD, so as to provide new insights into promising therapeutic targets for the abovementioned neurological conditions.
Highlights
Reactive oxygen species (ROS), an umbrella term for a category of active oxygen-containing compounds generated from aerobic metabolism [1], encompasses superoxide anion (O2−), hydrogen peroxide (H2O2), and free radical
It can positively regulate autophagy through the AMP-dependent protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway [147], which promotes neuronal survival within an in vitro oxygen and glucose (OGD) deprivation model of cerebral ischemia created by attenuating H2O2 and O2− [148]
Autophagic neuronal death will still result if cumulative Reactive Oxygen Species (ROS) go beyond the scavenging activity of autophagy
Summary
Reactive oxygen species (ROS), an umbrella term for a category of active oxygen-containing compounds generated from aerobic metabolism [1], encompasses superoxide anion (O2−), hydrogen peroxide (H2O2), and free radical (superoxide and hydroxyl radicals) Each of these compounds can damage biomacromolecules essential for various cellular processes [2], while simultaneously playing an indispensable role in the redox signaling cascade required for critically important biological events [3]. When there exists any redox imbalance between the generation and the scavenging of ROS, oxidative stress occurs, leading to unpredictable oxidative damage to organelles, proteins, lipids, and DNA, as well as the disruption of cellular structures and functions and eventually cell death [25] (Figure 1). ROS or oxidative stress level is usually measured by monitoring the activity of cellular antioxidant enzymes such as SOD and GSH-px, each of which can indirectly reflect the ability to remove ROS [27]. ROS elevation initiates neuronal damage and we propose that Nrf2-related agents look set to offer an up-and-coming clinical therapy
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