Takayama Ken-Ichi, Suzuki Takashi, Sato Kaoru, Saito Yuko, Inoue Satoshi
Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi, Tokyo, Japan.
Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Aging Cell. 2024 Dec;23(12):e14316. doi: 10.1111/acel.14316. Epub 2024 Aug 18.
Dysfunctional RNA-binding proteins (RBPs) have been implicated in several geriatric diseases, including Alzheimer's disease (AD). However, little is known about the nuclear molecular actions and cooperative functions mediated by RBPs that affect gene regulation in sporadic AD or aging. In the present study, we investigated aging- and AD-associated changes in the expression of PSF and G3BP2, which are representative RBPs associated with sex hormone activity. We determined that both PSF and G3BP2 levels were decreased in aged brains compared to young brains of mice. RNA sequencing (RNA-seq) analysis of human neuronal cells has shown that PSF is responsible for neuron-specific functions and sustains cell viability. In addition, we showed that PSF interacted with G3BP2 in the nucleus and stress granules (SGs) at the protein level. Moreover, PSF-mediated gene regulation at the RNA level correlated with G3BP2. Interestingly, PSF and G3BP2 target genes are associated with AD development. Mechanistically, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis demonstrated that the interaction of RBPs with the pre-mRNA of target genes enhanced post-transcriptional mRNA stability, suggesting a possible role for these RBPs in preserving neuronal cell viability. Notably, in the brains of patients with sporadic AD, decreased expression of PSF and G3BP2 in neurons was observed compared to non-AD patients. Overall, our findings suggest that the cooperative action of PSF and G3BP2 in the nucleus is important for preventing aging and AD development.
功能失调的RNA结合蛋白（RBPs）与包括阿尔茨海默病（AD）在内的多种老年疾病有关。然而，对于散发性AD或衰老过程中影响基因调控的RBPs介导的核分子作用和协同功能，我们知之甚少。在本研究中，我们调查了PSF和G3BP2表达与衰老和AD相关的变化，PSF和G3BP2是与性激素活性相关的代表性RBPs。我们确定，与小鼠的年轻大脑相比，老年大脑中PSF和G3BP2的水平均降低。对人类神经元细胞的RNA测序（RNA-seq）分析表明，PSF负责神经元特异性功能并维持细胞活力。此外，我们发现PSF在蛋白质水平上与G3BP2在细胞核和应激颗粒（SGs）中相互作用。此外，PSF在RNA水平上介导的基因调控与G3BP2相关。有趣的是，PSF和G3BP2的靶基因与AD的发展有关。从机制上讲，定量逆转录-聚合酶链反应（qRT-PCR）分析表明，RBPs与靶基因的前体mRNA相互作用可增强转录后mRNA的稳定性，这表明这些RBPs在维持神经元细胞活力方面可能发挥作用。值得注意的是，在散发性AD患者的大脑中，与非AD患者相比，观察到神经元中PSF和G3BP2的表达降低。总体而言，我们的研究结果表明，PSF和G3BP2在细胞核中的协同作用对于预防衰老和AD的发展很重要。
