Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content

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.

Automated summary

Rare genetic diseases affecting the nervous system are often caused by mutations in ATP7A and ATP7B genes, leading to disruptions in copper homeostasis. These disruptions can result in alterations in epidermis, aminergic, sensory, and motor neurons in Drosophila, with effects on mitochondrial content at synapses and synaptic morphology, transmission, and plasticity. The integrity of Golgi-dependent copper homeostasis mechanisms involving ATP7 and COG is crucial for maintaining mitochondrial function and synaptic localization.