The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation

Abstract

Neuronal loss is one of the striking causes of various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features and clinical manifestations, they share some common mechanisms of disease pathology. Progressive regional loss of neurons in patients is responsible for motor, memory, and cognitive dysfunctions, leading to disabilities and death. Neuronal cell death in neurodegenerative diseases is linked to various pathways and conditions. Protein misfolding and aggregation, mitochondrial dysfunction, generation of reactive oxygen species (ROS), and activation of the innate immune response are the most critical hallmarks of most common neurodegenerative diseases. Thus, endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation are the major pathological factors of neuronal cell death. Even though the exact mechanisms are not fully discovered, the notable role of mentioned factors in neuronal loss is well known. On this basis, researchers have been prompted to investigate the neuroprotective effects of targeting underlying pathways to determine a promising therapeutic approach to disease treatment. This review provides an overview of the role of ER stress, oxidative stress, and neuroinflammation in neuronal cell death, mainly discussing the neuroprotective effects of targeting pathways or molecules involved in these pathological factors.

Keywords: ER stress; ROS; UPR – unfolded protein response; cell death; neurodegenerative diseases; neuroinflammation; oxidative stress.

Figure 1

The role of three arms of UPR in inducing apoptosis and the neuroprotective effects of particular inhibitors (shown in yellow box). (A) The PERK pathway: interaction of substrate binding domain of BiP with misfolded or aggregated proteins leads to BiP dissociation, dimerization, and autophosphorylation of PERK, which further causes eIF2α phosphorylation. Phosphorylated eIF2α induces cell death by transcription of apoptotic factors by means of ATF4 transcription factor as well as inhibition of protein synthesis. (B) The IRE1 pathway: after dissociation of BiP from IRE1 receptor by misfolded or aggregated proteins in the ER lumen, IRE1 undergoes oligomerization and autophosphorylation. This results in mRNA degradation termed “regulated IRE1alpha-dependent decay” (RIDD) and inducing apoptotic factors by initiating JNK/MAPK cascade. To mitigate ER stress, the IRE1 pathway also leads to XBP1 mRNA splicing to transcript ER chaperones to improve ER machinery. (C) The ATF6 pathway: translocation of ATF6 to the Golgi apparatus as a result of BiP dissociation, and the proteolysis of ATF6 in Golgi brings out an activated ATF6 transcription factor to transcript ER chaperones and XBP1 for ER machinery.

Figure 2

Cause and consequences of ROS production in the CNS and the neuroprotective effects of inhibitory factors (shown in yellow box).

Figure 3

The possible role of inhibiting inflammatory factors to attenuate neuroinflammation-induced neuronal cell death.