A recent paper in Aging sheds light on stress granules' (SGs) role in Alzheimer's disease (AD). The study, conducted by researchers Kaoru Sato, Ken-ichi Takayama, and Satoshi Inoue from the Tokyo Metropolitan Institute for Geriatrics and Gerontology, uncovers a comprehensive RNA regulatory mechanism involving SGs that could potentially be targeted therapeutically to slow down AD progression mediated by SGs.
Previous research has shown that SGs, cytoplasmic membrane-less structures that can develop under stressful conditions, are linked to various neurodegenerative disorders, including AD. SGs contain translationally arrested mRNAs, suggesting impaired neuron RNA metabolism may contribute to AD progression. However, the underlying mechanism has remained unclear.
In this study, the researchers employed enhanced cross-linking and immunoprecipitation-sequencing (eCLIP-seq) to investigate the RNAs directly targeted by the SG core proteins G3BP1 and G3BP2. Their findings revealed that numerous mRNAs and long non-coding RNAs (lncRNAs) were bound by these proteins both before and after stress conditions. Notably, they discovered that AD-associated gene transcripts accumulated within SGs, implicating SGs' involvement in regulating AD development.
Through gene-network analysis, the researchers also uncovered a possible connection between the sequestration of RNAs by SGs and the impairment of protein neurohomeostasis in AD brains. The sequestered RNAs within SGs are longer, AT-rich transcripts and are implicated in the dysregulation of protein levels. These findings provide valuable insights into the RNA regulatory mechanism mediated by SGs and its potential role in AD pathology.
By targeting the SG-mediated RNA regulatory mechanism, it may be possible to slow down the progression of Alzheimer's disease. This research represents a significant step in unraveling the molecular mechanisms underlying AD pathogenesis and provides a foundation for future studies exploring novel therapeutic strategies.