Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan.
Integrated Research Initiative for Living Well with Dementia, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan.
Geriatr Gerontol Int. 2024 Mar;24 Suppl 1:7-14. doi: 10.1111/ggi.14663. Epub 2023 Sep 19.
Living organisms experience a range of stresses. To cope effectively with these stresses, eukaryotic cells have evolved a sophisticated mechanism involving the formation of stress granules (SGs), which play a crucial role in protecting various types of RNA species under stress, such as mRNAs and long non-coding RNAs (lncRNAs). SGs are non-membranous cytoplasmic ribonucleoprotein (RNP) granules, and the RNAs they contain are translationally stalled. Importantly, SGs have been thought to contribute to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). SGs also contain multiple RNA-binding proteins (RBPs), several of which have been implicated in AD progression. SGs are transient structures that dissipate after stress relief. However, the chronic stresses associated with aging lead to the persistent formation of SGs and subsequently to solid-like pathological SGs, which could impair cellular RNA metabolism and also act as a nidus for the aberrant aggregation of AD-associated proteins. In this paper, we provide a comprehensive summary of the physical basis of SG-enriched RNAs and SG-resident RBPs. We then review the characteristics of AD-associated gene transcripts and their similarity to the SG-enriched RNAs. Furthermore, we summarize and discuss the functional implications of SGs in neuronal RNA metabolism and the aberrant aggregation of AD-associated proteins mediated by SG-resident RBPs in the context of AD pathogenesis. Geriatr Gerontol Int 2024; 24: 7-14.
生物体经历着各种压力。为了有效地应对这些压力，真核细胞进化出了一种复杂的机制，涉及应激颗粒（SGs）的形成，SGs 在保护各种类型的 RNA 物种（如 mRNAs 和长非编码 RNA（lncRNAs））方面起着至关重要的作用。SGs 是非膜细胞质核糖核蛋白（RNP）颗粒，其包含的 RNA 处于翻译暂停状态。重要的是，SGs 被认为有助于神经退行性疾病（包括阿尔茨海默病（AD））的病理生理学。SGs 还包含多个 RNA 结合蛋白（RBPs），其中一些与 AD 的进展有关。SGs 是瞬态结构，在缓解压力后会消散。然而，与衰老相关的慢性压力会导致 SG 的持续形成，随后形成固态病理性 SGs，这可能会损害细胞 RNA 代谢，并作为 AD 相关蛋白异常聚集的核心。在本文中，我们全面总结了富含 SG 的 RNA 和 SG 驻留 RBPs 的物理基础。然后，我们回顾了 AD 相关基因转录本的特征及其与富含 SG 的 RNA 的相似性。此外，我们总结并讨论了 SG 在神经元 RNA 代谢中的功能意义以及 SG 驻留 RBPs 在 AD 发病机制中对 AD 相关蛋白异常聚集的影响。老年医学与老年病学 2024; 24: 7-14。
