Emerging Roles of Sestrins in Neurodegenerative Diseases: Counteracting Oxidative Stress and Beyond

Abstract

Low levels of reactive oxygen species (ROS) are critical for the operation of regular neuronal function. However, heightened oxidative stress with increased contents of oxidation markers in DNA, lipids, and proteins with compromised antioxidant capacity may play a harmful role in the brain and may be implicated in the pathophysiology of neurodegenerative diseases. Sestrins, a family of evolutionarily-conserved stress-inducible proteins, are actively regulated by assorted stresses, such as DNA damage, hypoxia, and oxidative stress. Three highly homologous genes that encode sestrin1, sestrin2, and sestrin3 proteins exist in the genomes of vertebrates. Under stressful conditions, sestrins are activated with versatile functions to cope with different types of stimuli. A growing body of evidence suggests that sestrins, especially sestrin2, can counteract oxidative stress, lessen mammalian/mechanistic target of rapamycin (mTOR) expression, and promote cell survival, thereby playing a critical role in aging-related disorders including neurodegeneration. Strategies capable of augmenting sestrin expression may; thus, facilitate cell adaptation to stressful conditions or environments through stimulation of antioxidant response and autophagy process, which may carry clinical significance in neurodegenerative diseases.

Keywords: autophagy; mTOR; neurodegenerative diseases; oxidative stress; sestrins.

Figure 1

Both exogenous and endogenous factors may induce superoxide ions, reactive oxygen species (ROS), and reactive nitrogen species (RNS) to insult proteins, DNA, and lipids, which may further lead to oxidative damage and thereby create a vicious cycle to promote pathogenesis of neurodegenerative diseases. However, this also opens possibilities of developing therapeutic treatments for these diseases.

Figure 2

The sestrin2–GATOR interaction triggered by oxidative stress regulates mTORC1 activity and downstream autophagy homeostasis.

Figure 3

The schematic diagram illustrates that sestrin2 induced by oxidative stress plays a central role in the maintenance of cellular homeostasis by regulating multiple mediators involved in anti-oxidation, metabolism, and cellular degradation (autophagy).