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. 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.

• Publication year

  2020

• Venue

  Journal of Neuroscience

• Publication date

  2020-05-23

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/2020.05.22.110627PMID 33208468PMCID PMC7810662
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Downregulation of COG complex subunits rescues the neuronal and synaptic phenotypes caused by ATP7 expression, supporting a Golgi-dependent copper homeostasis mechanism required for synaptic development and mitochondrial localization.

  Confidence 0.93

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• Transgenic ATP7 expression in Drosophila disrupts copper homeostasis and produces epidermal, aminergic, sensory, and motor neuron phenotypes, including reduced mitochondrial content at synapses.

  Confidence 0.94

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• ATP7 paralogs show genetic and biochemical interactions with the COG complex.

  Confidence 0.96

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review

• atp7 paralogs

  protein family

  Copper-transporting ATPase proteins ATP7A and ATP7B that localize to the Golgi apparatus in the biological context discussed here.

  Aliases: ATP7A, ATP7B, ATP7 proteins

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• cog complex

  protein complex

  The conserved oligomeric Golgi complex, a vesicular tether associated with Golgi organization and trafficking.

  Aliases: conserved oligomeric Golgi complex, COG

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• copper homeostasis

  biological process

  Cellular control of copper levels and distribution in the context of Golgi-linked copper handling.

  Aliases: copper regulation

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• golgi apparatus

  organelle

  The intracellular organelle where ATP7 proteins and the COG complex are described as acting in this paper.

  Aliases: Golgi, Golgi complex

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• mitochondrial content at synapses

  cellular phenotype

  The amount or abundance of mitochondria present at synaptic sites in neurons.

  Aliases: synaptic mitochondrial content, mitochondria at synapses

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review
• synaptic development

  developmental process

  The formation and maturation of synaptic structure and function during neuronal development.

  Aliases: synapse development

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewq (76h6bfydm6) review

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