Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, 82 Wood Lane, London W12 0BZ, U.K.
National Heart and Lung Institute, Imperial College London, Molecular Sciences Research Hub, 82 Wood Lane, London W12 0BZ, U.K.
ACS Chem Neurosci. 2024 Aug 7;15(15):2884-2896. doi: 10.1021/acschemneuro.4c00280. Epub 2024 Jul 16.
Copper homeostasis is critical to the functioning of the brain, and its breakdown is linked with many brain diseases. Copper is also known to interact with the negatively charged lipid, phosphatidylserine (PS), as well as α-synuclein, an aggregation-prone protein enriched in the synapse, which plays a role in synaptic vesicle docking and fusion. However, the interplay between copper, PS lipid, and α-synuclein is not known. Herein, we report a detailed and predominantly kinetic study of the interactions among these three components pertinent to copper homeostasis and neurotransmission. We found that synaptic vesicle-mimicking small unilamellar vesicles (SUVs) can sequester any excess free Cu within milliseconds, and bound Cu on SUVs can be reduced to Cu by GSH at a nearly constant rate under physiological conditions. Moreover, we revealed that SUV-bound Cu does not affect the binding between wild-type α-synuclein and SUVs but affect that between N-terminal acetylated α-synuclein and SUVs. In contrast, Cu can effectively displace both types of α-synuclein from the vesicles. Our results suggest that synaptic vesicles may mediate copper transfer in the brain, while copper could participate in synaptic vesicle docking to the plasma membrane via its regulation of the interaction between α-synuclein and synaptic vesicle.
铜稳态对大脑功能至关重要，其失衡与许多脑部疾病有关。铜还已知与带负电荷的磷脂酰丝氨酸 (PS) 以及富含突触的易聚集蛋白α-突触核蛋白相互作用，该蛋白在突触小泡的 docking 和融合中发挥作用。然而，铜、PS 脂质和α-突触核蛋白之间的相互作用尚不清楚。在此，我们报告了对与铜稳态和神经传递相关的这三个成分之间相互作用的详细和主要动力学研究。我们发现，模拟突触小泡的小单层囊泡 (SUVs) 可以在几毫秒内隔离任何多余的游离 Cu，并且在生理条件下，GSH 可以以几乎恒定的速率将 SUV 上的结合 Cu 还原为 Cu。此外，我们揭示了 SUV 结合的 Cu 不会影响野生型α-突触核蛋白与 SUV 之间的结合，但会影响 N 端乙酰化α-突触核蛋白与 SUV 之间的结合。相比之下，Cu 可以有效地将这两种类型的α-突触核蛋白从囊泡中置换出来。我们的结果表明，突触小泡可能介导大脑中的铜转移，而铜可能通过调节α-突触核蛋白与突触小泡之间的相互作用参与突触小泡与质膜的 docking。
