Lechler Marie C, Crawford Emily D, Groh Nicole, Widmaier Katja, Jung Raimund, Kirstein Janine, Trinidad Jonathan C, Burlingame Alma L, David Della C
German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany; Graduate Training Centre of Neuroscience, 72074 Tübingen, Germany.
German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.
Cell Rep. 2017 Jan 10;18(2):454-467. doi: 10.1016/j.celrep.2016.12.033.
Low-complexity "prion-like" domains in key RNA-binding proteins (RBPs) mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components, including stress granule proteins, become highly insoluble with age in C. elegans and that reduced insulin/insulin-like growth factor 1 (IGF-1) daf-2 receptor signaling efficiently prevents their aggregation. Importantly, stress-granule-related RBP aggregates are associated with reduced fitness. We show that heat shock transcription factor 1 (HSF-1) is a main regulator of stress-granule-related RBP aggregation in both young and aged animals. During aging, increasing DAF-16 activity restores dynamic stress-granule-related RBPs, partly by decreasing the buildup of other misfolded proteins that seed RBP aggregation. Longevity-associated mechanisms found to maintain dynamic RBPs during aging could be relevant for neurodegenerative diseases.
关键RNA结合蛋白（RBP）中低复杂性的“类朊病毒”结构域介导RNA颗粒的可逆组装。携带这些结构域的单个RBP与特定的神经退行性疾病有关。尽管它们在神经退行性变中的聚集已得到广泛表征，但衰老过程如何扰乱RBP动态变化仍不清楚。我们发现，包括应激颗粒蛋白在内的多种RNA颗粒成分在秀丽隐杆线虫中会随着年龄增长而变得高度不溶，而胰岛素/胰岛素样生长因子1（IGF-1）daf-2受体信号传导的减弱可有效防止它们聚集。重要的是，与应激颗粒相关的RBP聚集与健康状况下降有关。我们表明，热休克转录因子1（HSF-1）是年轻和年老动物中与应激颗粒相关的RBP聚集的主要调节因子。在衰老过程中，增加DAF-16活性可恢复与应激颗粒相关的动态RBP，部分原因是减少了引发RBP聚集的其他错误折叠蛋白的积累。在衰老过程中发现的与长寿相关的维持动态RBP的机制可能与神经退行性疾病有关。
