Anderton Edward, Chamoli Manish, Bhaumik Dipa, King Christina D, Xie Xueshu, Foulger Anna, Andersen Julie K, Schilling Birgit, Lithgow Gordon J
The Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945.
USC Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave., Los Angeles, CA 90191.
bioRxiv. 2023 Dec 9:2023.07.13.548937. doi: 10.1101/2023.07.13.548937.
Loss of proteostasis is a highly conserved feature of aging across model organisms and typically results in the accumulation of insoluble protein aggregates. Protein insolubility is a central feature of major age-related neurodegenerative diseases, including Alzheimer's Disease (AD), where hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Moreover, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven protein insolubility as a contributory factor. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. We demonstrate that Aβ expression drives proteome-wide protein insolubility in C. elegans and this insoluble proteome closely resembles the insoluble proteome driven by normal aging, suggesting the possibility of a vicious feedforward cycle of aggregation in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the CIP is enriched with proteins that modulate the toxic effects of Aβ and that the gut-derived metabolite, Urolithin A, relieves Aβ toxicity, supporting its use in clinical trials for dementia and other age-related diseases.
蛋白质稳态的丧失是跨模式生物衰老的一个高度保守特征，通常会导致不溶性蛋白质聚集体的积累。蛋白质不溶性是包括阿尔茨海默病（AD）在内的主要年龄相关性神经退行性疾病的核心特征，在AD中，数百种不溶性蛋白质与老年斑中的聚集淀粉样β蛋白（Aβ）相关联。此外，模式生物衰老过程中变得不溶的蛋白质能够在体外加速Aβ聚集。尽管衰老与AD风险之间存在联系，但迄今为止的治疗方法都忽略了衰老驱动的蛋白质不溶性这一促成因素。在这里，我们使用一种无偏见的蛋白质组学方法，探究了Aβ与年龄相关蛋白质不溶性之间的关系。我们证明，Aβ表达会导致秀丽隐杆线虫全蛋白质组范围内的蛋白质不溶性，并且这种不溶性蛋白质组与正常衰老驱动的不溶性蛋白质组非常相似，这表明在AD背景下存在聚集的恶性循环可能性。重要的是，通过人类全基因组关联研究（GWAS），我们表明与年龄相关的不溶性蛋白质组（CIP）不仅富含与神经退行性疾病有关的生物学过程，还涉及广泛的慢性、年龄相关疾病（CARDs）。这提供了暗示性证据，表明与年龄相关的蛋白质稳态丧失可能在一般CARD风险中起作用。最后，我们表明CIP富含调节Aβ毒性作用的蛋白质，并且肠道衍生的代谢产物尿石素A可减轻Aβ毒性，支持其在痴呆症和其他年龄相关疾病的临床试验中的应用。
