Alshareef Hussam Z, Ballinger Thomas, Rojas Everett, van der Linden Alexander M
Department of Biology, University of Nevada, Reno, NV, United States.
Front Aging Neurosci. 2025 Mar 24;17:1464015. doi: 10.3389/fnagi.2025.1464015. eCollection 2025.
Circular RNAs (circRNAs) are non-coding RNAs mostly derived from exons of protein-coding genes via a back-splicing process. The expression of hundreds of circRNAs accumulates during healthy aging and is associated with Alzheimer's disease (AD), which is characterized by the accumulation of amyloid-beta (Aβ) proteins. In , many circRNAs were previously found to accumulate during aging, with loss of age-accumulated circRNAs derived from the CREB gene (circ-) to increase mean lifespan. Here, we used to study the effects of age-accumulated circRNAs on the age-related onset of Aβ-toxicity. We found that circ- mutations delayed Aβ-induced muscle paralysis and lifespan phenotypes in a transgenic strain expressing a full-length human Aβ-peptide (Aβ) selectively in muscle cells (GMC101). The delayed Aβ phenotypic defects were associated with the inhibition of Aβ aggregate deposition, and thus, genetic removal of circ- alleviated Aβ-induced toxicity. Consistent with a detrimental role for age-accumulated circRNAs in AD, the expression level of circ- expression is elevated after induction of Aβ during aging, whereas linear mRNA expression remains unchanged. Finally, we found that the delayed onset of Aβ-induced paralysis observed in circ- mutants is dependent on the collagen gene. Taken together, our results show that the loss of an age-accumulated circRNA exerts a protective role on Aβ-induced toxicity, demonstrating the utility of for studying circRNAs in AD and its relationship to aging.
环状RNA（circRNAs）是非编码RNA，主要通过反向剪接过程从蛋白质编码基因的外显子产生。数百种circRNAs的表达在健康衰老过程中积累，并与阿尔茨海默病（AD）相关，AD的特征是淀粉样β（Aβ）蛋白的积累。在[具体内容缺失]中，先前发现许多circRNAs在衰老过程中积累，缺失源自CREB基因的随年龄积累的circRNAs（circ-）可延长平均寿命。在此，我们使用[具体内容缺失]来研究随年龄积累的circRNAs对与年龄相关的Aβ毒性发作的影响。我们发现，在肌肉细胞（GMC101）中选择性表达全长人Aβ肽（Aβ）的转基因[具体内容缺失]品系中，circ-突变延迟了Aβ诱导的肌肉麻痹和寿命表型。Aβ表型缺陷的延迟与Aβ聚集体沉积的抑制有关，因此，circ-的基因去除减轻了Aβ诱导的毒性。与随年龄积累的circRNAs在AD中起有害作用一致，衰老过程中诱导Aβ后circ-的表达水平升高，而线性[具体内容缺失]mRNA表达保持不变。最后，我们发现circ-突变体中观察到的Aβ诱导的麻痹发作延迟依赖于[具体内容缺失]胶原蛋白基因。综上所述，我们的结果表明，随年龄积累的circRNA的缺失对Aβ诱导的毒性发挥保护作用，证明了[具体内容缺失]在研究AD中的circRNAs及其与衰老关系方面的实用性。
