Celllular mechanisms of neuronal metal transport and toxicity

神经元金属转运和毒性的细胞机制

• 批准号: 8434528
• 负责人: Victor Faundez
• 金额: $ 37.98万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434528
• 关键词: Acute; Adaptor Signaling Protein; Address; Aging; Alleles; Alzheimer' 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; 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; public health relevance; receptor; reconstitution; relating to nervous system; toxicant; trafficking; uptake; zinc-binding protein

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（申请人提供）：神经元锌参与兴奋性神经传递调节等关键过程。相反，神经元特别容易受到这种金属过量的影响。为了平衡这些相反的作用，细胞具有精细控制胞质游离金属浓度的机制。在这些机制中，锌的细胞器金属固存稳态依赖于锌转运蛋白家族成员ZnT/SLC30。这些机制是这个应用程序的重点。ZnT/SLC30在神经元中的主要锌转运体是ZnT3。ZnT3位于突触囊泡中，其遗传缺陷可调节从癫痫到阿尔茨海默病的病理。在我们之前的资助期间，我们发现ZnT3的分布和锌的运输活性受其寡聚化控制