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 #
5R01GM077569-06
Application #
8599779
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Anderson, Vernon
Project Start
2006-04-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
$341,803
Indirect Cost
$121,778
Name
Emory University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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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
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Zlatic, Stephanie; Comstra, Heather Skye; Gokhale, Avanti et al. (2015) Molecular basis of neurodegeneration and neurodevelopmental defects in Menkes disease. Neurobiol Dis 81:154-61
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
Evstratova, Alesya; Chamberland, Simon; Faundez, Victor et al. (2014) Vesicles derived via AP-3-dependent recycling contribute to asynchronous release and influence information transfer. Nat Commun 5:5530

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