Stress-induced condensation of TDP-43 in the nucleus

TDP-43 is an RNA-binding protein ubiquitously dysregulated in neurodegeneration. We found that under stress conditions, TDP-43 undergoes reversible condensation in the nucleus of cultured cells including human neurons. These condensates (“TCs”) are non-liquid assemblies with low dynamic properties. Their proteomic analysis and subsequent comparison with the normal (soluble) TDP-43 interactome revealed that upon condensate partitioning, TDP-43 dissociates from its normal protein binding partners. We propose that the main function of TCs is rapid but reversible inactivation of TDP-43 during stress. This can help fine-tune the splicing patterns under stress to enable efficient stress response and survival.

TDP-43是一类在神经退行性疾病中普遍失调的RNA结合蛋白。我们发现，在应激条件下，TDP-43可在包括人神经元在内的培养细胞的细胞核中发生可逆凝聚。这类凝聚体（TCs）属于具有低动态特性的非液态组装体。通过对其开展蛋白质组学分析，并与正常（可溶性）TDP-43的相互作用组进行后续比对，我们发现：当TDP-43被招募至凝聚体中后，其会从自身正常的蛋白结合伴侣上解离下来。我们提出假说，TCs的主要功能是在应激过程中对TDP-43实现快速且可逆的失活。该过程可帮助在应激状态下微调基因剪接模式，从而实现高效的应激应答与细胞存活。