Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, S-171 76 Stockholm, Sweden.
Metallomics. 2024 May 2;16(5). doi: 10.1093/mtomcs/mfae019.
Common features of neurodegenerative diseases are oxidative and inflammatory imbalances as well as the misfolding of proteins. An excess of free metal ions can be pathological and contribute to cell death, but only copper and zinc strongly promote protein aggregation. Herein we demonstrate that the endogenous copper-binding tripeptide glycyl-l-histidyl-l-lysine (GHK) has the ability to bind to and reduce copper redox activity and to prevent copper- and zinc-induced cell death in vitro. In addition, GHK prevents copper- and zinc-induced bovine serum albumin aggregation and reverses aggregation through resolubilizing the protein. We further demonstrate the enhanced toxicity of copper during inflammation and the ability of GHK to attenuate this toxicity. Finally, we investigated the effects of copper on enhancing paraquat toxicity and report a protective effect of GHK. We therefore conclude that GHK has potential as a cytoprotective compound with regard to copper and zinc toxicity, with positive effects on protein solubility and aggregation that warrant further investigation in the treatment of neurodegenerative diseases.
神经退行性疾病的共同特征是氧化和炎症失衡以及蛋白质错误折叠。过量的游离金属离子可能是病理性的，并导致细胞死亡，但只有铜和锌能强烈促进蛋白质聚集。本文中，我们证明了内源性铜结合三肽甘氨酰-L-组氨酰-L-赖氨酸（GHK）具有结合和降低铜氧化还原活性的能力，并能预防体外铜和锌诱导的细胞死亡。此外，GHK 可防止铜和锌诱导的牛血清白蛋白聚集，并通过重新溶解蛋白质来逆转聚集。我们进一步证明了炎症过程中铜的毒性增强以及 GHK 减轻这种毒性的能力。最后，我们研究了铜对增强百草枯毒性的影响，并报告了 GHK 的保护作用。因此，我们得出结论，GHK 具有作为铜和锌毒性的细胞保护化合物的潜力，对蛋白质的可溶性和聚集具有积极影响，值得在神经退行性疾病的治疗中进一步研究。
