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Cover ArticleResearch Articles, Cellular/Molecular

Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content

Cortnie Hartwig, Gretchen Macías Méndez, Shatabdi Bhattacharjee, Alysia D. Vrailas-Mortimer, Stephanie A. Zlatic, Amanda A. H. Freeman, Avanti Gokhale, Mafalda Concilli, Erica Werner, Christie Sapp Savas, Samantha Rudin-Rush, Laura Palmer, Nicole Shearing, Lindsey Margewich, Jacob McArthy, Savanah Taylor, Blaine Roberts, Vladimir Lupashin, Roman S. Polishchuk, Daniel N. Cox, Ramon A. Jorquera and Victor Faundez
Journal of Neuroscience 13 January 2021, 41 (2) 215-233; DOI: https://doi.org/10.1523/JNEUROSCI.1284-20.2020
Cortnie Hartwig
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Gretchen Macías Méndez
2Neuroscience Department, Universidad Central del Caribe, Bayamon, Puerto Rico 00956
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Shatabdi Bhattacharjee
3Neuroscience Institute, Center for Behavioral Neuroscience, Georgia State University, Atlanta, Georgia 30302
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Alysia D. Vrailas-Mortimer
4School of Biological Sciences, IL State University, Normal, Illinois 617901
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Stephanie A. Zlatic
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Amanda A. H. Freeman
5The Center for the Study of Human Health, Emory University, Atlanta, Georgia 30322
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Avanti Gokhale
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Mafalda Concilli
6Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy
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Erica Werner
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Christie Sapp Savas
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Samantha Rudin-Rush
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Laura Palmer
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Nicole Shearing
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Lindsey Margewich
4School of Biological Sciences, IL State University, Normal, Illinois 617901
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Jacob McArthy
4School of Biological Sciences, IL State University, Normal, Illinois 617901
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Savanah Taylor
4School of Biological Sciences, IL State University, Normal, Illinois 617901
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Blaine Roberts
7Departments of Biochemistry, Emory University, Atlanta, Georgia 30322
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Vladimir Lupashin
8Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
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Roman S. Polishchuk
6Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy
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Daniel N. Cox
3Neuroscience Institute, Center for Behavioral Neuroscience, Georgia State University, Atlanta, Georgia 30302
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Ramon A. Jorquera
2Neuroscience Department, Universidad Central del Caribe, Bayamon, Puerto Rico 00956
9Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
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Victor Faundez
1Departments of Cell Biology, Emory University, Atlanta, Georgia 30322
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Abstract

Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the conserved oligomeric Golgi (COG) complex, a Golgi apparatus vesicular tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. Prominent among neuronal phenotypes was a decreased mitochondrial content at synapses, a phenotype that paralleled with alterations of synaptic morphology, transmission, and plasticity. These neuronal and synaptic phenotypes caused by transgenic expression of ATP7 were rescued by downregulation of COG complex subunits. We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses.

SIGNIFICANCE STATEMENT Menkes and Wilson disease affect copper homeostasis and characteristically afflict the nervous system. However, their molecular neuropathology mechanisms remain mostly unexplored. We demonstrate that copper homeostasis in neurons is maintained by two factors that localize to the Golgi apparatus, ATP7 and the conserved oligomeric Golgi (COG) complex. Disruption of these mechanisms affect mitochondrial function and localization to synapses as well as neurotransmission and synaptic plasticity. These findings suggest communication between the Golgi apparatus and mitochondria through homeostatically controlled cellular copper levels and copper-dependent enzymatic activities in both organelles.

  • ATP7A
  • copper
  • Golgi
  • Menkes
  • mitochondria
  • Wilson

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The Journal of Neuroscience: 41 (2)
Journal of Neuroscience
Vol. 41, Issue 2
13 Jan 2021
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Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content
Cortnie Hartwig, Gretchen Macías Méndez, Shatabdi Bhattacharjee, Alysia D. Vrailas-Mortimer, Stephanie A. Zlatic, Amanda A. H. Freeman, Avanti Gokhale, Mafalda Concilli, Erica Werner, Christie Sapp Savas, Samantha Rudin-Rush, Laura Palmer, Nicole Shearing, Lindsey Margewich, Jacob McArthy, Savanah Taylor, Blaine Roberts, Vladimir Lupashin, Roman S. Polishchuk, Daniel N. Cox, Ramon A. Jorquera, Victor Faundez
Journal of Neuroscience 13 January 2021, 41 (2) 215-233; DOI: 10.1523/JNEUROSCI.1284-20.2020

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Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content
Cortnie Hartwig, Gretchen Macías Méndez, Shatabdi Bhattacharjee, Alysia D. Vrailas-Mortimer, Stephanie A. Zlatic, Amanda A. H. Freeman, Avanti Gokhale, Mafalda Concilli, Erica Werner, Christie Sapp Savas, Samantha Rudin-Rush, Laura Palmer, Nicole Shearing, Lindsey Margewich, Jacob McArthy, Savanah Taylor, Blaine Roberts, Vladimir Lupashin, Roman S. Polishchuk, Daniel N. Cox, Ramon A. Jorquera, Victor Faundez
Journal of Neuroscience 13 January 2021, 41 (2) 215-233; DOI: 10.1523/JNEUROSCI.1284-20.2020
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Keywords

  • ATP7A
  • copper
  • Golgi
  • Menkes
  • mitochondria
  • Wilson

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