Research Paper Volume 15, Issue 10 pp 3984—4011

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

Kaoru Sato1,2, , Ken-ichi Takayama1, , Satoshi Inoue1, ,

  • 1 Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology (TMIG), Itabashi-ku, Tokyo 173-0015, Japan
  • 2 Integrated Research Initiative for Living Well with Dementia (IRIDE), TMIG, Itabashi-ku, Tokyo 173-0015, Japan

Received: March 24, 2023       Accepted: April 28, 2023       Published: May 22, 2023
How to Cite

Copyright: © 2023 Sato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


AD: Alzheimer’s disease; AS: Sodium arsenite; CDS: Coding sequence; CLIP: Cross-linking and immunoprecipitation; eCLIP-seq: Enhanced cross-linking and immunoprecipitation-sequencing; ECM: Extracellular matrix; G3BP: Ras-GTPase-activating protein SH3-domain-binding protein; KD RNA-seq: Knockdown RNA sequencing; LncRNA: long non-coding RNA; NB: Neuroblastoma; SG: Stress granule; SG RNA-seq: Stress granule RNA sequencing; UTR: Untranslated region.