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.

Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system

“…The downregulation of COG complex subunits can rescue the altered synaptic phenotypes. These results collectively support the critical role of Golgi and Cu in neurodegeneration and neurodevelopmental disorders [ 131 ].…”

“…Evidenced by using the Drosophila model, Hartwig et al demonstrated that interactions between ATP7 paralogs and COG complex, a Golgi apparatus vesicular tether, are essential to maintain Cu homeostasis in neurons. Disruption of ATP7–COG complex interaction affects COG-mediated TGN proteins recycling in motor neurons, which is similar to manipulating the expression level of ATP7 paralogs, leading to the perturbation of Cu homeostasis, decreased synaptic mitochondria content and altered synapse plasticity [ 131 ].…”

“…These regulators include, but are not limited to, Rab22, clathrin coat protein, adaptor protein complexes AP-1/AP-2, retromer complex subunit VPS35, the WASH complex, sorting nexin, ADP-ribosylation factor 1 (ARF1) and the COG complex (see summary in table 2). These regulators play essential roles in cargo sorting and the formation of shuttling vesicles between endosomes and Golgi complex as well as Golgi tethering [115][116][117][118]130,131,141,181]. It is worth noting that none of these regulators has been reported to possess Cu-responsive motifs.…”

Sulfur- and phosphorus-standardized metal quantification of biological specimens using inductively coupled plasma mass spectrometry

“…This protocol bypasses challenges because of limited sample amounts and facilitates studies examining the biological roles of metals in health and disease. For complete details on the use and execution of this protocol, please refer to Hartwig et al. (2020) .…”

“…For complete details on the use and execution of this protocol, please refer to Hartwig et al. (2020) .…”