Celllular mechanisms of neuronal metal transport and toxicity

神经元金属转运和毒性的细胞机制

基本信息

批准号：
8786564
负责人：
Victor Faundez
金额：
$ 37.98万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786564
关键词：
Acute Adaptor Signaling Protein Address Aging Alleles Alzheimer&apos s Disease Binding Catalysis Cell membrane Cell physiology Cells Chronic Complex Data Dimerization Disease Endosomes Enzymes Epilepsy Equilibrium Extracellular Space Family member Funding Generations Genetic Health Hereditary Disease Hippocampus (Brain)Homeostasis Hydrogen Peroxide In Vitro Knock-in Mouse Knowledge Maps Mediating Membrane Membrane Proteins Metals Modification Molecular Molecular Chaperones Mus Mutant Strains Mice Mutate Mutation NADPH Oxidase Nerve Neurons Organelles Oxidation-Reduction PC12 Cells Pathologic Processes Pathology Pathway interactions Phenylalanine Play Post-Translational Protein Processing Predisposition Process Resistance Role Sorting - Cell Movement Source Synapses Synaptic Vesicles System Testing Therapeutic Intervention Toxic effect Trauma Tyrosine Vesicle Zinc Zinc Fingers Zinc deficiency chelation dimer dityrosine excitotoxicity gain of function in vivo kainate loss of function loss of function mutation metal poisoning mouse model mutant nervous system disorder neuronal cell body neurotoxicity neurotransmission novel protein complex protein folding receptor reconstitution relating to nervous system toxicant trafficking uptake zinc-binding protein

项目摘要

DESCRIPTION (provided by applicant): Neuronal zinc participates in key processes such as modulation of excitatory neurotransmission. In contrast, neurons are particularly susceptible to excess of this metal. To balance these opposing effects, cells possess mechanisms to finely control free cytoplasmic metal concentration. Among these mechanisms, zinc homeostasis by organelle metal sequestration relies on ZnT/SLC30 zinc transporter family members. These mechanisms are the focus of this application. The main ZnT/SLC30 zinc transporter in neurons is ZnT3. ZnT3 is located in synaptic vesicles and its genetic deficiency modulates pathology ranging from epilepsy to Alzheimer's disease. During our previous funding period, we discovered that ZnT3 distribution and zinc transport activity are controlled by its oligomerization state. ZnT3 dimers confer cellular resistance to zinc toxicity by an inter-ZnT3 dityrosine bond whose generation is catalyzed by redox mechanisms. This is the first example of a membrane protein regulated by dityrosine bonds. We propose that compartment-specific ZnT3 transporter oligomerization by redox mechanisms regulates metal toxicity resistance. In this application, we test this hypothesis in vitro and in vivo using dimerization gain- and loss-of-function mutations i ZnT3 as well as mice carrying deficiencies or gain-of-function in the ZnT3 trafficking and transport pathways. Our studies will impact our understanding and possibly treatment of acute and chronic neurological disease processes where zinc play a role such as epilepsy and Alzheimer's disease.

描述（由申请人提供）：神经元锌参与关键过程，例如兴奋性神经传递的调节。相反，神经元特别容易受到过量这种金属的影响。为了平衡这些相反的作用，细胞拥有精细控制游离细胞质金属浓度的机制。在这些机制中，通过细胞器金属螯合实现的锌稳态依赖于 ZnT/SLC30 锌转运蛋白家族成员。这些机制是本应用的重点。神经元中主要的 ZnT/SLC30 锌转运蛋白是 ZnT3。 ZnT3 位于突触小泡中，其遗传缺陷可调节从癫痫到阿尔茨海默氏病的病理学。在我们之前的资助期间，我们发现 ZnT3 分布和锌转运活性受其低聚控制状态。 ZnT3 二聚体通过 ZnT3 间二酪氨酸键赋予细胞对锌毒性的抵抗力，该键的生成由氧化还原机制催化。这是受二酪氨酸键调节的膜蛋白的第一个例子。我们提出，隔室特异性 ZnT3 转运蛋白通过氧化还原机制寡聚可调节金属毒性抵抗力。在本申请中，我们使用 ZnT3 的二聚化获得和功能丧失突变以及 ZnT3 运输和运输途径中携带缺陷或功能获得的小鼠在体外和体内测试了这一假设。我们的研究将影响我们对锌在癫痫和阿尔茨海默氏病等急性和慢性神经系统疾病过程中发挥作用的理解和可能的治疗。