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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Neurotoxicology and Alcohol Study Section (NAL)
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Anderson, Vernon
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Emory University
Anatomy/Cell Biology
Schools of Medicine
United States
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