Department of Chemistry, University of Houston, Houston, TX 77204, USA.
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Open Biol. 2021 Dec;11(12):210128. doi: 10.1098/rsob.210128. Epub 2021 Dec 1.
Imbalanced copper homeostasis and perturbation of membrane trafficking are two common symptoms that have been associated with the pathogenesis of neurodegenerative and neurodevelopmental diseases. Accumulating evidence from biophysical, cellular and studies suggest that membrane trafficking orchestrates both copper homeostasis and neural functions-however, a systematic review of how copper homeostasis and membrane trafficking interplays in neurons remains lacking. Here, we summarize current knowledge of the general trafficking itineraries for copper transporters and highlight several critical membrane trafficking regulators in maintaining copper homeostasis. We discuss how membrane trafficking regulators may alter copper transporter distribution in different membrane compartments to regulate intracellular copper homeostasis. Using Parkinson's disease and MEDNIK as examples, we further elaborate how misregulated trafficking regulators may interplay parallelly or synergistically with copper dyshomeostasis in devastating pathogenesis in neurodegenerative diseases. Finally, we explore multiple unsolved questions and highlight the existing challenges to understand how copper homeostasis is modulated through membrane trafficking.
铜稳态失衡和膜运输紊乱是与神经退行性和神经发育性疾病发病机制相关的两个常见症状。来自生物物理、细胞和 研究的大量证据表明，膜运输协调铜稳态和神经功能——然而，关于铜稳态和膜运输如何相互作用于神经元的系统综述仍然缺乏。在这里，我们总结了铜转运体一般运输途径的现有知识，并强调了几个关键的膜运输调节剂在维持铜稳态中的作用。我们讨论了膜运输调节剂如何改变不同膜区室中铜转运体的分布，以调节细胞内铜稳态。我们以帕金森病和 MEDNIK 为例，进一步阐述了失调的运输调节剂如何与神经退行性疾病中破坏性发病机制中的铜稳态失调平行或协同相互作用。最后，我们探讨了多个未解决的问题，并强调了现有挑战，以了解铜稳态如何通过膜运输进行调节。
