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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077569-07
Application #
8786564
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Anderson, Vernon
Project Start
2006-04-01
Project End
2015-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Emory University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Monis, William J; Faundez, Victor; Pazour, Gregory J (2017) BLOC-1 is required for selective membrane protein trafficking from endosomes to primary cilia. J Cell Biol 216:2131-2150
Devergnas, Annaelle; Chen, Erdong; Ma, Yuxian et al. (2016) Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys. J Neurophysiol 115:470-85
Delevoye, Cédric; Heiligenstein, Xavier; Ripoll, Léa et al. (2016) BLOC-1 Brings Together the Actin and Microtubule Cytoskeletons to Generate Recycling Endosomes. Curr Biol 26:1-13
Gokhale, Avanti; Hartwig, Cortnie; Freeman, Amanda H et al. (2016) The Proteome of BLOC-1 Genetic Defects Identifies the Arp2/3 Actin Polymerization Complex to Function Downstream of the Schizophrenia Susceptibility Factor Dysbindin at the Synapse. J Neurosci 36:12393-12411
Gokhale, Avanti; Ryder, Pearl V; Zlatic, Stephanie A et al. (2016) Identification of the Interactome of a Palmitoylated Membrane Protein, Phosphatidylinositol 4-Kinase Type II Alpha. Methods Mol Biol 1376:35-42
Arnold, Miranda; Cross, Rebecca; Singleton, Kaela S et al. (2016) The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin. Front Cell Neurosci 10:218
Gokhale, Avanti; Vrailas-Mortimer, Alysia; Larimore, Jennifer et al. (2015) Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet 24:5512-23
Gokhale, Avanti; Mullin, Ariana P; Zlatic, Stephanie A et al. (2015) The N-ethylmaleimide-sensitive factor and dysbindin interact to modulate synaptic plasticity. J Neurosci 35:7643-53
Mullin, Ariana P; Sadanandappa, Madhumala K; Ma, Wenpei et al. (2015) Gene dosage in the dysbindin schizophrenia susceptibility network differentially affect synaptic function and plasticity. J Neurosci 35:325-38
Marzolo, María-Paz; Faundez, Victor; Galli, Thierry (2015) EMBO workshop al fin del mundo: a meeting on membrane trafficking and its implication for polarity and diseases. Biol Cell 107:245-8

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