Xiangyu Teng, Ewelina Stefaniak, Keith R Willison, Liming Ying
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引用次数: 0
摘要
铜的平衡对大脑的功能至关重要,铜的失衡与许多脑部疾病有关。铜还与带负电荷的脂质磷脂酰丝氨酸(PS)以及α-突触核蛋白相互作用,α-突触核蛋白是一种富含在突触中的易聚集蛋白,在突触小泡对接和融合中发挥作用。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,我们报告了对这三种与铜平衡和神经传递有关的成分之间相互作用的详细和主要动力学研究。我们发现,在生理条件下,模拟突触小泡的单层小泡(SUVs)能在几毫秒内封存任何多余的游离 Cu2+,SUVs 上的结合 Cu2+ 能以几乎恒定的速度被 GSH 还原成 Cu+。此外,我们发现 SUV 结合的 Cu2+ 不会影响野生型 α-synuclein 与 SUV 之间的结合,但会影响 N 端乙酰化的 α-synuclein 与 SUV 之间的结合。相反,Cu2+ 能有效地将两种类型的α-突触核蛋白从囊泡中置换出来。我们的研究结果表明,突触小泡可能在大脑中介导铜的转移,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对接。
Interplay between Copper, Phosphatidylserine, and α-Synuclein Suggests a Link between Copper Homeostasis and Synaptic Vesicle Cycling.
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 Cu2+ within milliseconds, and bound Cu2+ on SUVs can be reduced to Cu+ by GSH at a nearly constant rate under physiological conditions. Moreover, we revealed that SUV-bound Cu2+ 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, Cu2+ 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.
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research