Horio Tomoyo, Ishikura Yui, Ohashi Rie, Shiina Nobuyuki
Laboratory of Neuronal Cell Biology, National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan.
Department of Basic Biology, Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi 444-8585, Japan.
Heliyon. 2023 Jun 7;9(6):e17065. doi: 10.1016/j.heliyon.2023.e17065. eCollection 2023 Jun.
In neurodegenerative diseases, the condensation of FUS and TDP-43 with RNA granules in neurons is linked to pathology, including synaptic disorders. However, the effects of FUS and TDP-43 on RNA granule factors remain unclear. Here, using primary cultured neurons from the mouse cerebral cortex, we show that excess cytoplasmic FUS and TDP-43 accumulated in dendritic RNA granules, where they increased the dynamics of a scaffold protein RNG105/caprin1 and dissociated it from the granules. This coincided with reduced levels of mRNA and translation around the granules and synaptic loss in dendrites. These defects were suppressed by non-dissociable RNG105, suggesting that RNG105 dissociation mediated the defects. In contrast to the model where FUS and TDP-43 co-aggregate with RNA granule factors to repress their activity, our findings provide a novel pathogenic mechanism whereby FUS and TDP-43 dissociate RNA scaffold proteins from RNA granules which are required for local translation that regulates synapse formation.
在神经退行性疾病中，神经元内FUS和TDP - 43与RNA颗粒的凝聚与病理学相关，包括突触紊乱。然而，FUS和TDP - 43对RNA颗粒因子的影响仍不清楚。在此，我们使用从小鼠大脑皮层原代培养的神经元，发现过量的细胞质FUS和TDP - 43积聚在树突状RNA颗粒中，它们增加了支架蛋白RNG105/caprin1的动态变化，并使其从颗粒中解离。这与颗粒周围mRNA水平和翻译的降低以及树突中的突触丢失相吻合。这些缺陷被不可解离的RNG105抑制，表明RNG105的解离介导了这些缺陷。与FUS和TDP - 43与RNA颗粒因子共同聚集以抑制其活性的模型不同，我们的研究结果提供了一种新的致病机制，即FUS和TDP - 43使RNA支架蛋白从调节突触形成的局部翻译所需的RNA颗粒中解离。
