Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
J Biol Chem. 2022 Jul;298(7):102088. doi: 10.1016/j.jbc.2022.102088. Epub 2022 May 30.
The gut microbiome has been shown to have key implications in the pathogenesis of Parkinson's disease (PD). The Escherichia coli functional amyloid CsgA is known to accelerate α-synuclein aggregation in vitro and induce PD symptoms in mice. However, the mechanism governing CsgA-mediated acceleration of α-synuclein aggregation is unclear. Here, we show that CsgA can form stable homodimeric species that correlate with faster α-synuclein amyloid aggregation. Furthermore, we identify and characterize new CsgA homologs encoded by bacteria present in the human microbiome. These CsgA homologs display diverse aggregation kinetics, and they differ in their ability to modulate α-synuclein aggregation. Remarkably, we demonstrate that slowing down CsgA aggregation leads to an increased acceleration of α-synuclein aggregation, suggesting that the intrinsic amyloidogenicity of gut bacterial CsgA homologs affects their ability to accelerate α-synuclein aggregation. Finally, we identify a complex between CsgA and α-synuclein that functions as a platform to accelerate α-synuclein aggregation. Taken together, our work reveals complex interplay between bacterial amyloids and α-synuclein that better informs our understanding of PD causation.
肠道微生物组已被证明对帕金森病（PD）的发病机制有重要影响。已知大肠杆菌功能型淀粉样蛋白 CsgA 可加速α-突触核蛋白在体外聚集，并在小鼠中诱导 PD 症状。然而，CsgA 介导的α-突触核蛋白聚集加速的机制尚不清楚。在这里，我们表明 CsgA 可以形成稳定的同源二聚体，与更快的α-突触核蛋白淀粉样聚集相关。此外，我们鉴定并表征了存在于人类微生物组中的细菌编码的新 CsgA 同源物。这些 CsgA 同源物显示出不同的聚集动力学，并且在调节α-突触核蛋白聚集的能力上存在差异。值得注意的是，我们证明了减缓 CsgA 聚集会导致α-突触核蛋白聚集的加速增加，这表明肠道细菌 CsgA 同源物的固有淀粉样特性会影响它们加速α-突触核蛋白聚集的能力。最后，我们鉴定了 CsgA 和α-突触核蛋白之间的复合物，该复合物作为加速α-突触核蛋白聚集的平台发挥作用。总之，我们的工作揭示了细菌淀粉样蛋白和α-突触核蛋白之间的复杂相互作用，这使我们更好地了解了 PD 的病因。
