Department of Chemistry , Indian Institute of Technology , Delhi, Hauz-Khas, New Delhi 110016 , India.
ACS Chem Neurosci. 2018 Jun 20;9(6):1477-1491. doi: 10.1021/acschemneuro.8b00056. Epub 2018 Apr 6.
Aggregation of α-synuclein is closely connected to the pathology of Parkinson's disease. The phenomenon involves multiple steps, commenced by partial misfolding and eventually leading to mature amyloid fibril formation. Trehalose, a widely accepted osmolyte, has been shown previously to inhibit aggregation of various globular proteins owing to its ability to prevent the initial unfolding of protein. In this study, we have examined if it behaves in a similar fashion with intrinsically disordered protein α-synuclein and possesses the potential to act as therapeutic agent against Parkinson's disease. It was observed experimentally that samples coincubated with trehalose fibrillate faster compared to the case in its absence. Molecular dynamics simulations suggested that this initial acceleration is manifestation of trehalose's tendency to perturb the conformational transitions between different conformers of monomeric protein. It stabilizes the aggregation prone "extended" conformer of α-synuclein, by binding to its exposed acidic residues of the C terminus. It also favors the β-rich oligomers once formed. Interestingly, the total fibrils formed are still promisingly less since it accelerates the competing pathway toward formation of amorphous aggregates.
α-突触核蛋白的聚集与帕金森病的病理学密切相关。这一现象涉及多个步骤，首先是部分错误折叠，最终导致成熟的淀粉样纤维形成。海藻糖是一种被广泛认可的渗透调节剂，先前已被证明能够抑制各种球状蛋白的聚集，因为它能够防止蛋白的初始展开。在这项研究中，我们研究了它是否以类似的方式与无规卷曲蛋白 α-突触核蛋白相互作用，并具有作为治疗帕金森病的潜在药物的能力。实验观察到，与没有海藻糖的情况相比，与海藻糖共孵育的样品更快地纤维化。分子动力学模拟表明，这种初始加速是海藻糖倾向于扰乱单体蛋白不同构象之间构象转变的表现。它通过与 C 端暴露的酸性残基结合来稳定易聚集的“伸展”构象的α-突触核蛋白。它还有利于形成富含β的低聚物。有趣的是，由于它加速了形成无定形聚集体的竞争途径，因此形成的总纤维仍然令人充满希望地减少。
