Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Rare genetic diseases, including Menkes and Wilson disease, often manifest as neurodevelopmental or neurodegenerative disorders.
• These conditions are linked to mutations in ATP7A and ATP7B, proteins critical for copper homeostasis and localized to the Golgi apparatus.

Purpose of the Study:

• To investigate the molecular mechanisms underlying neurodegeneration in copper homeostasis disorders.
• To explore the interaction between ATP7 proteins and the conserved oligomeric Golgi (COG) complex in maintaining neuronal health.

Main Methods:

• Genetic and biochemical analyses were performed to study ATP7 paralogs and the COG complex.
• Tissue-specific transgenic expression of ATP7 in *Drosophila* was used to model copper homeostasis disruption.
• Neuronal and synaptic phenotypes were assessed, including mitochondrial content, morphology, transmission, and plasticity.

Main Results:

• Disruption of copper homeostasis via ATP7 expression in *Drosophila* led to epidermal and neuronal alterations, notably decreased synaptic mitochondria.
• Synaptic morphology, transmission, and plasticity were impaired in affected neurons.
• Downregulation of COG complex subunits rescued the observed neuronal and synaptic phenotypes.

Conclusions:

• The integrity of Golgi-dependent copper homeostasis, involving ATP7 and COG, is essential for maintaining mitochondrial function and synaptic localization.
• These findings highlight a critical link between the Golgi apparatus, cellular copper levels, and mitochondrial health in neurons.
• This research provides insights into the neuropathology of Menkes and Wilson diseases and suggests a communication pathway between the Golgi and mitochondria.