Watanabe Yasuaki, Suzuki Naoki, Nakagawa Tadashi, Hosogane Masaki, Akiyama Tetsuya, Kageyama Naotoshi, Funayama Yukino, Warita Hitoshi, Morimoto Satoru, Okano Hideyuki, Aoki Masashi, Nakayama Keiko
Department of Neurology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, 980-8575, Japan.
Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, 980-8575, Japan.
EMBO J. 2025 Jul 24. doi: 10.1038/s44318-025-00506-0.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons. Although multiple pathophysiological mechanisms have been identified, no comprehensive understanding of these heterogeneous processes has been achieved. The ALS-associated RNA-binding protein (RBP) TDP-43 has previously been shown to stabilize UNC13A mRNA by preventing cryptic exon inclusion. Here, we show that the ALS-associated RBPs MATR3, FUS, and hnRNPA1 regulate UNC13A expression by targeting the transcriptional repressor REST. These RBPs bind to and downregulate REST mRNA to promote UNC13A transcription. Loss of any of these RBPs in cultured cells or in iPSC-derived motor neurons carrying the ALS-causing FUS P525L mutation leads to REST overexpression, and the same is observed in motor neurons of individuals with familial or sporadic ALS. The functional convergence of four RBPs on the regulation of UNC13A expression underscores the important role of this process for synaptic integrity, and its association with ALS pathogenesis could be relevant for the development of new therapeutic agents.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元选择性丧失。尽管已经确定了多种病理生理机制，但尚未对这些异质性过程有全面的了解。此前已表明，与ALS相关的RNA结合蛋白（RBP）TDP-43通过防止隐蔽外显子包含来稳定UNC13A mRNA。在此，我们表明，与ALS相关的RBPs MATR3、FUS和hnRNPA1通过靶向转录抑制因子REST来调节UNC13A的表达。这些RBPs与REST mRNA结合并下调其表达，以促进UNC13A转录。在携带导致ALS的FUS P525L突变的培养细胞或诱导多能干细胞衍生的运动神经元中，这些RBPs中的任何一种缺失都会导致REST过表达，在家族性或散发性ALS患者的运动神经元中也观察到同样的情况。四种RBPs在调节UNC13A表达上的功能趋同强调了这一过程对突触完整性的重要作用，其与ALS发病机制的关联可能与新型治疗药物的开发有关。
