Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy.
Department of Experimental Medical Science, Lund University, 221 84, Lund, Sweden.
Biometals. 2018 Aug;31(4):551-559. doi: 10.1007/s10534-018-0101-y. Epub 2018 Apr 5.
Specific mutations in APOA1 gene lead to systemic, hereditary amyloidoses. In ApoA-I related amyloidosis involving the heart, amyloid deposits are mainly constituted by the 93-residue N-terminal region of the protein, here indicated as [1-93]ApoA-I. Oxidative stress is known to be an enhancing factor for protein aggregation. In healthy conditions, humans are able to counteract the formation and the effects of oxidative molecules. However, aging and atmospheric pollution increase the concentration of oxidative agents, such as metal ions. As the main effect of iron deregulation is proposed to be an increase in oxidative stress, we analysed the effects of iron on [1-93]ApoA-I aggregation. By using different biochemical approaches, we demonstrated that Fe(II) is able to reduce the formation of [1-93]ApoA-I fibrillar species, probably by stabilizing its monomeric form, whereas Fe(III) shows a positive effect on polypeptide fibrillogenesis. We hypothesize that, in healthy conditions, Fe(III) is reduced by the organism to Fe(II), thus inhibiting amyloid formation, whereas during ageing such protective mechanisms decline, thus exposing the organism to higher oxidative stress levels, which are also related to an increase in Fe(III). This alteration could contribute to the pathogenesis of amyloidosis.
特定的 APOA1 基因突变会导致系统性遗传性淀粉样变性。在涉及心脏的 ApoA-I 相关淀粉样变性中，淀粉样沉积物主要由蛋白质的 93 个残基 N 端区域组成，这里表示为[1-93]ApoA-I。氧化应激已知是促进蛋白质聚集的因素。在健康状态下，人体能够抵抗氧化分子的形成和作用。然而，衰老和大气污染会增加氧化剂（如金属离子）的浓度。由于铁失调的主要影响被认为是增加氧化应激，我们分析了铁对[1-93]ApoA-I 聚集的影响。通过使用不同的生化方法，我们证明 Fe(II)能够减少[1-93]ApoA-I 纤维状物质的形成，可能是通过稳定其单体形式，而 Fe(III)对多肽原纤维形成显示出积极的影响。我们假设，在健康状态下，Fe(III)被机体还原为 Fe(II)，从而抑制淀粉样形成，而在衰老过程中，这种保护机制下降，从而使机体暴露于更高的氧化应激水平，这也与 Fe(III)的增加有关。这种改变可能有助于淀粉样变性的发病机制。
