PDF(Pubmed)
Abstract：
Amyloid formation by α-synuclein (αSyn) occurs in Parkinson\'s disease, multiple system atrophy, and dementia with Lewy bodies. Deciphering the residues that regulate αSyn amyloid fibril formation will not only provide mechanistic insight but may also reveal targets to prevent and treat disease. Previous investigations have identified several regions of αSyn to be important in the regulation of amyloid formation, including the non-amyloid-β component (NAC), P1 region (residues 36 to 42), and residues in the C-terminal domain. Recent studies have also indicated the importance of the N-terminal region of αSyn for both its physiological and pathological roles. Here, the role of residues 2 to 7 in the N-terminal region of αSyn is investigated in terms of their ability to regulate amyloid fibril formation in vitro and in vivo. Deletion of these residues (αSynΔN7) slows the rate of fibril formation in vitro and reduces the capacity of the protein to be recruited by wild-type (αSynWT) fibril seeds, despite cryo-EM showing a fibril structure consistent with those of full-length αSyn. Strikingly, fibril formation of αSynΔN7 is not induced by liposomes, despite the protein binding to liposomes with similar affinity to αSynWT. A Caenorhabditis elegans model also showed that αSynΔN7::YFP forms few puncta and lacks motility and lifespan defects typified by expression of αSynWT::YFP. Together, the results demonstrate the involvement of residues 2 to 7 of αSyn in amyloid formation, revealing a target for the design of amyloid inhibitors that may leave the functional role of the protein in membrane binding unperturbed.
摘要：
α-突触核蛋白（αSyn）的淀粉样蛋白形成发生在帕金森病中，多系统萎缩,和路易体痴呆症。破译调节αSyn淀粉样蛋白原纤维形成的残基将不仅提供机械见解，而且还可能揭示预防和治疗疾病的靶标。先前的研究已经确定了αSyn的几个区域在淀粉样蛋白形成的调节中很重要，包括非淀粉样β成分（NAC），P1区（残基36至42），和C端结构域中的残基。最近的研究还表明αSyn的N末端区域对于其生理和病理作用的重要性。这里,根据其在体外和体内调节淀粉样蛋白原纤维形成的能力，研究了αSynN末端区域中残基2至7的作用。这些残基（αSynΔN7）的缺失减慢了体外原纤维形成的速率，并降低了野生型（αSynWT）原纤维种子募集蛋白质的能力，尽管cryo-EM显示出与全长αSyn一致的原纤维结构。引人注目的是，αSynΔN7的原纤维形成不是由脂质体诱导的，尽管蛋白质以与αSynWT相似的亲和力与脂质体结合。秀丽隐杆线虫模型还显示，αSyntΔN7::YFP形成很少的斑点，缺乏运动和寿命缺陷，以αSynWT::YFP的表达为代表。一起,结果表明，αSyn的残基2至7参与淀粉样蛋白的形成，揭示了淀粉样蛋白抑制剂设计的目标，该目标可能使蛋白质在膜结合中的功能作用不受干扰。
