Stress Granules and Neurodegenerative Disorders: A Scoping Review

Abstract

Cytoplasmic ribonucleoproteins called stress granules (SGs) are considered as one of the main cellular solutions against stress. Their temporary presence ends with stress relief. Any factor such as chronic stress or mutations in the structure of the components of SGs that lead to their permanent presence can affect their interactions with pathological aggregations and increase the degenerative effects. SGs involved in RNA mechanisms are important factors in the pathophysiology of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and Alzheimer's diseases (AD). Although many studies have been performed in the field of SGs and neurodegenerative disorders, so far, no systematic studies have been executed in this field. The purpose of this study is to provide a comprehensive perspective of all studies about the role of SGs in the pathogenesis of neurodegenerative disorders with a focus on the protein ingredients of these granules. This scoping review is based on a six-stage methodology structure and the PRISMA guideline. A systematic search of seven databases for qualified articles was conducted until December 2020. Publications were screened independently by two reviewers and quantitative and qualitative analysis was performed on the extracted data. Bioinformatics analysis was used to plot the network and predict interprotein interactions. In addition, GO analysis was performed. A total of 48 articles were identified that comply the inclusion criteria. Most studies on neurodegenerative diseases have been conducted on ALS, AD, and FTD using human post mortem tissues. Human derived cell line studies have been used only in ALS. A total 29 genes of protein components of SGs have been studied, the most important of which are TDP-43, TIA-1, PABP-1. Bioinformatics studies have predicted 15 proteins to interact with the protein components of SGs, which may be the constituents of SGs. Understanding the interactions between SGs and pathological aggregations in neurodegenerative diseases can provide new targets for treatment of these disorders.

Keywords: Alzheimer's; PABP-1; TDP-43; TIA-1; amyotrophic lateral sclerosis; neurodegenerative disorders; pathological aggregations; stress granules.

Figure 1

Search strategy flow chart based on the PRISMA flow diagram.

Figure 2

Protein-Protein Interactions and Top 10 GO analysis of target genes in SGs protein components in neurodegenerative disease. The network of neurodegenerative diseases with protein components of SGs and their interactions. (A) Gene ontology analysis of the genes in Table 2 (B) and Table 3 (C) has been performed. The length of each bar represents the degree of significance in that particular category sorted by p-value. Note that the lower the color intensity of the bars, the greater the relationship with that category.

Figure 3

Pathological Stress Granules Formation. (A) The cell is in equilibrium, and as stress arrives, nuclear depletion of SGs components occurs, the translation process halts and the structure of transient SGs is formed. Once the stress is relieved, the cell returns to normal and SGs disassemble. (B) The cell is exposed to acute stress, the components of SGs and protein aggregations (FUS and TDP-43) localize to the cytoplasm. In this condition, FUS and TDP-43 aggregations have not become pathological and do not interact with SGs, the number of SGs decreases as stress is relieved. (C) Under chronic stress, FUS and TDP-43 aggregations become pathological and in interaction with SGs, under the constant presence, pathological effects appear.

Figure 4

The interactions between SGs protein components and predicted proteins and GO analysis on predicted ones in neurodegenerative disease. (A) Fifteen new proteins were predicted by interaction with SGs protein components using the Cytoscape string-db plugin on data extracted from articles. (B) Fifteen new proteins were predicted by interaction with SGs protein components using the Cytoscape string-db plugin on data extracted from articles. GO analysis was performed on the predicted proteins in three biological processes: molecular function and cellular component. The length of each bar indicates the importance in that particular category sorted by p-value. Note that the lower the color intensity of the bars, the greater the relationship with that category.