Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, EAN, Oeiras 2784-505, Portugal.
Int J Mol Sci. 2013 Sep 17;14(9):19128-45. doi: 10.3390/ijms140919128.
Superoxide dismutase 1 (SOD1) aggregation is one of the pathological markers of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The underlying molecular grounds of SOD1 pathologic aggregation remains obscure as mutations alone are not exclusively the cause for the formation of protein inclusions. Thus, other components in the cell environment likely play a key role in triggering SOD1 toxic aggregation in ALS. Recently, it was found that ALS patients present a specific altered metabolomic profile in the cerebrospinal fluid (CSF) where SOD1 is also present and potentially interacts with metabolites. Here we have investigated how some of these small molecules affect apoSOD1 structure and aggregation propensity. Our results show that as co-solvents, the tested small molecules do not affect apoSOD1 thermal stability but do influence its tertiary interactions and dynamics, as evidenced by combined biophysical analysis and proteolytic susceptibility. Moreover, these compounds influence apoSOD1 aggregation, decreasing nucleation time and promoting the formation of larger and less soluble aggregates, and in some cases polymeric assemblies apparently composed by spherical species resembling the soluble native protein. We conclude that some components of the ALS metabolome that shape the chemical environment in the CSF may influence apoSOD1 conformers and aggregation.
超氧化物歧化酶 1（SOD1）聚集是肌萎缩侧索硬化症（ALS）的一种病理标志物，这是一种致命的神经退行性疾病。尽管突变并不是导致蛋白质包涵体形成的唯一原因，但 SOD1 病理性聚集的潜在分子基础仍然不清楚。因此，细胞环境中的其他成分可能在 ALS 中触发 SOD1 毒性聚集中发挥关键作用。最近发现，ALS 患者的脑脊液（CSF）中存在特定的代谢组学改变，SOD1 也存在于 CSF 中，并可能与代谢物相互作用。在这里，我们研究了这些小分子中的一些如何影响apoSOD1 的结构和聚集倾向。我们的结果表明，作为共溶剂，测试的小分子不会影响 apoSOD1 的热稳定性，但会影响其三级相互作用和动力学，这可以通过结合生物物理分析和蛋白水解敏感性来证明。此外，这些化合物影响 apoSOD1 的聚集，减少成核时间并促进形成更大且更不溶的聚集体，在某些情况下，聚合体显然由类似可溶性天然蛋白的球形物质组成。我们得出结论，ALS 代谢组的一些成分塑造了 CSF 中的化学环境，可能会影响 apoSOD1 构象和聚集。
