Kallweit Lena, Hamlett Eric D, Saternos Hannah, Gilmore Anah, Granholm Ann-Charlotte, Horowitz Scott
Department of Chemistry & Biochemistry and the Knoebel Institute for Healthy Aging, University of Denver, 2155 E Wesley Ave, Denver, CO 80208, USA.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425 USA.
bioRxiv. 2025 Jan 13:2023.10.02.560545. doi: 10.1101/2023.10.02.560545.
As the world population ages, new molecular targets in aging and Alzheimer's Disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. METHODS: In this study, we examined human hippocampal tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD.
We found that rG4 immunostaining strongly increased in the hippocampus with both age and with AD severity. We further found that neurons with accumulation of phospho-tau immunostaining contained rG4s, that rG4 structure can drive tau aggregation, and that rG4 staining density depended on APOE genotype in the human tissue examined.
Combined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation is linked to proteostasis collapse. These morphological findings suggest that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.
随着世界人口老龄化，需要新的衰老和阿尔茨海默病（AD）分子靶点来应对预期新增的AD病例。到目前为止，RNA结构在衰老和神经退行性变中的作用在很大程度上仍未被探索。
在本研究中，我们检测了人类海马组织中衰老和AD状态下RNA G-四链体（rG4s）的形成情况。
我们发现，rG4免疫染色在海马体中随着年龄增长和AD严重程度的增加而显著增强。我们进一步发现，磷酸化tau免疫染色阳性的神经元中含有rG4s，rG4结构可驱动tau聚集，并且在所检测的人体组织中，rG4染色密度取决于APOE基因型。
结合先前显示rG4结构依赖于应激以及rG4s在寡聚化蛋白质方面具有强大作用的研究，我们提出了一种神经退行性变模型，其中慢性rG4形成与蛋白质稳态崩溃相关。这些形态学发现表明，进一步研究神经退行性变中的RNA结构是未来治疗和诊断的关键途径。
