Depart of Biology and Biochemistry, University of Bath, Claverton Down, BA2 7AY, United Kingdom.
Depart of Biology and Biochemistry, University of Bath, Claverton Down, BA2 7AY, United Kingdom.
J Mol Biol. 2020 Dec 4;432(24):166706. doi: 10.1016/j.jmb.2020.11.005. Epub 2020 Nov 11.
Aggregation of α-Synuclein (αS) is widely regarded as a key factor in neuronal cell death, leading to a wide range of synucleinopathies, including Parkinson's Disease. Development of therapeutics has therefore focused on inhibiting aggregation of αS into toxic forms. One such inhibitor, based on the preNAC region αS (4554W), was identified using an intracellular peptide library screen, and subsequently shown to both inhibit formation of αS aggregates while simultaneously lowering toxicity. Subsequent efforts have sought to determine the mode of 4554W action. In particular, and consistent with the fact that both target and peptide are co-produced during library screening, we find that the peptide inhibits primary nucleation of αS, but does not modulate downstream elongation or secondary nucleation events. These findings hold significant promise towards mechanistic understanding and development of molecules that can module the first steps in αS aggregation towards novel treatments for Parkinson's disease and related synucleinopathies.
α-突触核蛋白（αS）的聚集被广泛认为是神经元细胞死亡的关键因素，导致广泛的突触核蛋白病，包括帕金森病。因此，治疗方法的开发重点集中在抑制 αS 聚集形成毒性形式上。一种这样的抑制剂是基于前 NAC 区的 αS（4554W），使用细胞内肽文库筛选来鉴定，随后显示它既能抑制 αS 聚集的形成，又能降低毒性。随后的研究旨在确定 4554W 的作用模式。特别是，与在文库筛选过程中目标和肽都共同产生的事实一致，我们发现该肽抑制 αS 的原始成核，但不调节下游的延伸或二级成核事件。这些发现为理解和开发能够调节 αS 聚集的第一个步骤的分子提供了重要的前景，这些分子可以为帕金森病和相关的突触核蛋白病提供新的治疗方法。
