Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content.

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.

• Authors: 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: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 41 Issue 2 Pg. 215-233 (01 13 2021) ISSN: 1529-2401 [Electronic] United States
• PMID: 33208468 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the authors.

Chemical References

• ATP7 protein, Drosophila
• RNA, Small Interfering
• Copper
• Adenosine Triphosphatases
• Copper-Transporting ATPases

Topics

• Adenosine Triphosphatases (metabolism)
• Animals
• Animals, Genetically Modified
• Cell Line
• Copper (physiology, toxicity)
• Copper-Transporting ATPases (genetics)
• Drosophila
• Electric Stimulation
• Extracellular Space (metabolism)
• Female
• Golgi Apparatus (physiology)
• Homeostasis (physiology)
• Humans
• Male
• Organelle Biogenesis
• RNA, Small Interfering
• Synapses (physiology, ultrastructure)