Stress granules sequester Alzheimer’s disease-associated gene transcripts and regulate disease-related neuronal proteostasis

Abstract

Environmental and physiological stresses can accelerate Alzheimer’s disease (AD) pathogenesis. Under stress, a cytoplasmic membraneless structure termed a stress granule (SG) is formed and is associated with various neurodegenerative disorders, including AD. SGs contain translationally arrested mRNAs, suggesting that impaired RNA metabolism in neurons causes AD progression; however, the underlying mechanism remains unclear. Here, we identified numerous mRNAs and long non-coding RNAs that are directly targeted by the SG core proteins G3BP1 and G3BP2. They redundantly target RNAs before and after stress conditions. We further identified RNAs within SGs, wherein AD-associated gene transcripts accumulated, suggesting that SGs can directly regulate AD development. Furthermore, gene-network analysis revealed a possible link between the sequestration of RNAs by SGs and the impairment of protein neurohomeostasis in AD brains. Together, our study provides a comprehensive RNA regulatory mechanism involving SGs, which could be targeted therapeutically to slow AD progression mediated by SGs.

Stress granule‐mediated RNA regulatory mechanism in Alzheimer's disease

“…34,41 In contrast, the length of lncRNAs shows a less obvious correlation with concentration at SGs than that of mRNAs, but longer transcripts have more RBP-binding sites, suggesting that the transcript length plays an important role even in concentrating lncRNAs at SGs. 34 Also, the presence of lncRNAs in SGs supports the idea that prior translation per se is not required for the accumulation of RNAs in SGs. 41,42 In addition to the longer transcript length, SG-enriched mRNAs have a lower GC content, which is also referred to as being adenine and uracil (AU)-rich, which is a common feature observed for poorly translated mRNAs.…”

“…[52][53][54][55][56][57][58] Enhanced crosslinking and immunoprecipitationsequencing (eCLIP-seq), a high-throughput technology for identifying RNA-binding protein targets, has shown that both G3BP1 and G3BP2 proteins bind to most SG-enriched RNAs, suggesting that these SG core proteins indeed play a major role in the loading of RNAs into SGs. 34 Notably, the changes in the RNA binding profiles for G3BP1 and G3BP2 detected by the eCLIP-seq technology are modest before and after stress, suggesting that even under non-stress conditions, both SG core proteins bind to their target RNAs to be ready for sudden stress to protect these RNAs. 34 In support of this, it has been shown that a protein interaction network of SGs is already present under non-stressed conditions, allowing for the rapid assembly of large SGs under stress.…”

“…34,40,41 Approximately 80-90% of SG-enriched RNAs are mRNAs, namely gene transcripts, and some lncRNAs can also accumulate in SGs. 34,41 Thousands of different mRNAs can be localized into SGs, but the distribution of their population may differ, largely depending on the overall transcriptome of the cell type. 34 Meanwhile, within the same cell type, these mRNAs show similar distributions even under different stresses, such as oxidative stress, endoplasmic reticulum (ER) stress, and heat shock.…”

“…48,59 Regulation of RNA metabolism by SGresident proteins in AD pathogenesis A number of AD-associated gene transcripts, including APP and MAPT, are sequestered to SGs in human neuronal cells. 34 SG core proteins, G3BP1 and G3BP2, interact directly with the APP mRNAs. 34 In addition, other SG-resident RBP, splicing factor proline and glutamine rich (SFPQ), 60 also known as polypyrimidine tract-binding protein-associated splicing factor (PSF), interacts with the APP transcript to maintain its mRNA stability in human neuronal cells 61 (Fig.…”

“…34 SG core proteins, G3BP1 and G3BP2, interact directly with the APP mRNAs. 34 In addition, other SG-resident RBP, splicing factor proline and glutamine rich (SFPQ), 60 also known as polypyrimidine tract-binding protein-associated splicing factor (PSF), interacts with the APP transcript to maintain its mRNA stability in human neuronal cells 61 (Fig. 4).…”