Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content

• Type of Material: Article
• Authors: Cortnie Hartwig, Emory University; Gretchen Macías Méndez, Universidad Central del Caribe; Shatabdi Bhattacharjee, Georgia State University; Alysia D Vrailas-Mortimer, IL State University; Stephanie Zlatic, Emory University; Amanda Freeman, Emory University; Avanti Gokhale, Emory University; Mafalda Concilli, Telethon Inst Genet & Med TIGEM; Erica Werner, Emory University; Christie Sapp Savas, Emory University; Samantha Rudin-Rush, Emory University; Laura Palmer, Emory University; Nicole Shearing, Emory University; Lindsey Margewich, IL State University; Jacob McArthy, IL State University; Savanah Taylor, IL State University; Blaine Roberts, Emory University; Vladimir Lupashin, University of Arkansas Medical Sciences; Roman S Polishchuk, Telethon Inst Genet & Med TIGEM; Daniel N Cox, Georgia State University; Ramon A Jorquera, Universidad Central del Caribe; Victor Faundez, Emory University
• Language: English
• Date: 2021-01-13
• Publisher: SOC NEUROSCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 the authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.1284-20.2020
• Title of Journal or Parent Work: JOURNAL OF NEUROSCIENCE
• Volume: 41
• Issue: 1
• Start Page: 215
• End Page: 233
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH) Grants 1RF1AG060285 (to V.F.), R01NS108778 and R01NS108778-01S1 (to R.A.J.), R15AR070505 (to A.D.V.-M.), Telethon TIGEM-CBDM9 (to R.S.P.), R01NS086082 (to D.N.C.), R01GM083144 (to V.L.), and 5K12GM000680-19 (to C.H.). Stocks obtained from the Bloomington Drosophila Stock Center (NIH Grant P40OD018537) were used in this study.
• Keywords: MACULAR MUTANT MOUSE; DROSOPHILA; Menkes; ATP7A; POSTTETANIC POTENTIATION; CALCIUM-CHANNELS; Wilson; DAMAGED MITOCHONDRIA; Neurosciences & Neurology; KINKY HAIR DISEASE; copper; EVOLUTIONARY RATE COVARIATION; CONSERVED OLIGOMERIC GOLGI; NERVOUS-SYSTEM; mitochondria; Neurosciences; GENETIC-DEFECTS; Science & Technology; Golgi; Life Sciences & Biomedicine
• Research Categories: Chemistry, Biochemistry; Biology, Cell

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.