The in vivo physiological function of liquid–liquid phase separation (LLPS) that governs non–membrane-bound structures remains elusive. Among LLPS-prone proteins, TAR DNA-binding protein of 43 kD (TDP-43) is under intense investigation because of its close association with neurological disorders. Here, we generated mice expressing endogenous LLPS-deficient murine TDP-43. LLPS-deficient TDP-43 mice demonstrate impaired neuronal function and behavioral abnormalities specifically related to brain function. Brain neurons of these mice, however, did not show TDP-43 proteinopathy or neurodegeneration. Instead, the global rate of protein synthesis was found to be greatly enhanced by TDP-43 LLPS loss. Mechanistically, TDP-43 LLPS ablation increased its association with PABPC4, RPS6, RPL7, and other translational factors. The physical interactions between TDP-43 and translational factors relies on a motif, the deletion of which abolished the impact of LLPS-deficient TDP-43 on translation. Our findings show a specific physiological role for TDP-43 LLPS in the regulation of brain function and uncover an intriguing novel molecular mechanism of translational control by LLPS.

中文翻译：

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TDP-43 相分离对大脑的翻译调节

控制非膜结合结构的液-液相分离（LLPS）的体内生理功能仍然难以捉摸。在易发生 LLPS 的蛋白质中，43 kD 的 TAR DNA 结合蛋白 (TDP-43) 由于与神经系统疾病密切相关而受到密切研究。在这里，我们生成了表达内源性 LLPS 缺陷的小鼠 TDP-43 的小鼠。LLPS 缺陷的 TDP-43 小鼠表现出神经元功能受损和与脑功能特别相关的行为异常。然而，这些小鼠的脑神经元并未表现出 TDP-43 蛋白病或神经变性。相反，发现 TDP-43 LLPS 损失大大提高了总体蛋白质合成率。从机制上讲，TDP-43 LLPS 消融增加了其与 PABPC4、RPS6、RPL7 和其他翻译因子的关联。TDP-43 和翻译因子之间的物理相互作用依赖于一个基序，该基序的删除消除了 LLPS 缺陷的 TDP-43 对翻译的影响。我们的研究结果显示了 TDP-43 LLPS 在调节大脑功能中的特定生理作用，并揭示了 LLPS 翻译控制的有趣的新颖分子机制。