Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China.
Biology Department, Clark University, Worcester, MA, USA.
FEBS Lett. 2022 Jun;596(11):1388-1400. doi: 10.1002/1873-3468.14361. Epub 2022 May 6.
The aggregation of α-synuclein (α-Syn) is a key pathological hallmark of Parkinson's disease (PD). α-Syn undergoes liquid-liquid phase separation (LLPS) to drive amyloid aggregation. How the LLPS of α-Syn is regulated remains largely unknown. Here, we discovered that the C-terminal region modulates α-Syn phase separation through electrostatic interactions. The wild-type (WT) and PD disease-related truncated α-Syn can co-exist in the condensates. The truncated α-Syn could dramatically promote WT α-Syn phase separation. Further studies demonstrated that the truncated α-Syn accelerated WT α-Syn turning to amyloid aggregates by modulation of phase separation. Together, our findings disclose the role of the C-terminal domain in the LLPS of α-Syn and pave the path for understanding the mechanism of truncated α-Syn in PD pathology.
α-突触核蛋白（α-Syn）的聚集是帕金森病（PD）的关键病理标志。α-Syn 通过液-液相分离（LLPS）驱动淀粉样蛋白聚集。α-Syn 的 LLPS 如何被调节在很大程度上仍然未知。在这里，我们发现 C 端区域通过静电相互作用调节 α-Syn 的相分离。野生型（WT）和与 PD 相关的截断的 α-Syn 可以在凝聚物中共存。截断的 α-Syn 可以显著促进 WT α-Syn 的相分离。进一步的研究表明，截断的 α-Syn 通过调节相分离加速 WT α-Syn 向淀粉样纤维的转变。总之，我们的研究结果揭示了 C 端结构域在 α-Syn 的 LLPS 中的作用，并为理解截断的 α-Syn 在 PD 病理学中的机制铺平了道路。
