Studies of SLC41A1, a Mg2+-Transporting Protein Linked to Parkinson's Disease

SLC41A1（一种与帕金森病相关的 Mg2 转运蛋白）的研究

• 批准号: 10711860
• 负责人: Lejla Zubcevic
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711860
• 关键词: Artificial Membranes; Binding; Binding Sites; Biological Assay; Biophysics; Carrier Proteins; Cell Line; Cell physiology; Cells; Cellular Assay; Chemicals; Collaborations; Coupled; Cryoelectron Microscopy; Data; Disease; Ensure; Functional disorder; Genes; Grant; Health; Health system; Homeostasis; Housekeeping; Human; Investigation; Ion Channel; Ion Transport; Ions; Knock-out; Lipid Bilayers; Liposomes; Luciferases; Magnesium; Measures; Mediating; Membrane; Membrane Potentials; Metabolism; Mitochondria; Modeling; Molecular; Mutation; Nerve Degeneration; Neurobiology; Neuroblastoma; Neurodegenerative Disorders; Neurons; Oxidative Phosphorylation; Parkinson Disease; Pathogenesis; Permeability; Prevention strategy; Production; Proteins; Research; Resolution; Risk; Role; Sequence Alignment; Site-Directed Mutagenesis; Structure; Testing; Time; Water; Work; conformational conversion; cost; design; dopaminergic neuron; experimental study; fluorescence imaging; link protein; member; mitochondrial membrane; negative affect; new therapeutic target; novel; professor; reconstitution; solute; virtual

Project Summary/Abstract Magnesium has been largely overlooked in neurobiology as a “housekeeping” ion, but this view is directly challenged by evidence which shows that mutations in Mg2+ transporting proteins are associated with neurodegeneration. Mutations in the Mg2+ transporting protein SLC41A1 are associated with both increased and decreased risk of Parkinson's disease (PD). SLC41A1 might therefore be a causative gene for PD. Despite this, little is known about SLC41A1. For example, we do not yet know if it causes rapid changes in free cytosolic Mg2+ (like an ion channel) or if it works to maintain the levels of free cytosolic Mg2+ within the range required for normal cellular function (like a transporter). This distinction is required both to define the role of SLC41A1 in the Mg2+ homeostasis and its role in PD pathogenesis. Furthermore, a cellular role for SLC41A1 has not been determined and it is therefore not known how its dysfunction might lead to PD. We hypothesize that SLC41A1 is a Mg2+-permeable ion channel which, through its role in maintaining the cellular Mg2+ homeostasis, helps maintain the mitochondrial membrane potential and ensures that ATP production via oxidative phosphorylation proceeds undisturbed. In this application for a Stephen I. Katz ESI grant, we propose to use liposomal flux assays and lipid bilayer studies as well as electron cryo-microscopy (cryo-EM) to determine how SLC41A1 mediates Mg2+ transport, and to generate a model to determine its cellular role. Neuronal Mg2+ transport has thus far been virtually untouched by biophysical and structural investigation and the study proposed here represents the first steps towards understanding the molecular mechanisms of neuronal Mg2+ homeostasis as well as the Mg2+-dependent molecular origins of neurodegenerative disorders. In the long term, this study of SLC41A1 has the potential to lead to novel treatments of and preventative strategies against PD, a debilitating disease which costs the US health system more than $14 billion each year.

项目总结/摘要 在神经生物学中，镁作为一种“管家”离子在很大程度上被忽视了，但这种观点直接 有证据表明，Mg 2+转运蛋白中的突变与 神经变性Mg 2+转运蛋白SLC 41 A1的突变与Mg 2+转运蛋白的增加和 降低帕金森病（PD）的风险。因此，SLC 41 A1可能是PD的致病基因。尽管如此， 目前对SLC 41 A1的了解还不多。例如，我们还不知道它是否会导致细胞内游离Mg 2+的快速变化。 (like离子通道），或者如果它能将游离胞浆Mg 2+水平维持在正常细胞所需的范围内， 细胞功能（如转运蛋白）。这种区别是需要的，以定义SLC 41 A1在Mg 2+中的作用， 稳态及其在PD发病机制中作用。此外，SLC 41 A1的细胞作用尚未确定 因此不知道其功能障碍如何导致PD。 我们假设SLC 41 A1是一个Mg 2+可渗透的离子通道，通过其在维持细胞增殖中的作用， 细胞Mg 2+稳态，有助于维持线粒体膜电位，并确保ATP 通过氧化磷酸化的生产不受干扰地进行。在斯蒂芬一世的申请中。Katz ESI 格兰特，我们建议使用脂质体通量测定和脂质双层研究以及电子冷冻显微镜 （cryo-EM）以确定SLC 41 A1如何介导Mg 2+转运，并产生模型以确定其细胞内的Mg 2+转运。 作用 迄今为止，神经元Mg 2+转运几乎未被生物物理学和结构研究所触及 这里提出的研究代表了理解分子机制的第一步， 神经元Mg 2+稳态以及神经退行性疾病的Mg 2+依赖性分子起源。在 从长远来看，这项对SLC 41 A1的研究有可能导致新的治疗和预防策略。 PD是一种使人衰弱的疾病，每年花费美国卫生系统超过140亿美元。