Context-dependent ATP7 Interactions with Parkinson's Disease-associated Genes Modulate Copper Homeostasis Phenotypes.
Brooke M Allen1, Nadia Gonzalez2,3, Erica Werner4
1Illinois State University, School of Biological Sciences, Normal, IL, USA.
Biorxiv : the Preprint Server for Biology
|February 12, 2026
Summary
Copper transporter gene mutations link to neurodegeneration. We found Parkinson's disease-associated Lrrk2 gene interactions with copper genes, revealing sex-specific effects on neuroprotection and copper toxicity.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Copper is vital for enzymes but toxic at high levels.
- Mutations in ATP7A/ATP7B copper transporters cause neurodegeneration.
- ATP7A interactome is linked to Parkinson's disease (PD) and neurodegeneration genes.
Purpose of the Study:
- To investigate genetic interactions between ATP7 mutants and PD/neurodegeneration genes.
- To understand the functional outcomes of ATP7A-PD gene interactions.
- To explore sex-specific differences in these interactions.
Main Methods:
- Used Drosophila as a model organism.
- Performed genetic interaction screens with ATP7 mutants and PD-associated genes.
- Analyzed sex-specific phenotypic effects.
Main Results:
- Identified sex differences in how candidate genes affect ATP7 phenotypes.
- Lrrk2 (Leucine-rich repeat kinase 2) protects against ATP7 dysfunction, especially in males.
- Lrrk2 influences intracellular copper toxicity in dopaminergic neurons in a sex-specific manner (females only).
Conclusions:
- ATP7A and PD-associated genes exhibit context-dependent interactions.
- These interactions play a role in maintaining copper homeostasis.
- Findings highlight sex-specific mechanisms in neurodegeneration linked to copper metabolism.
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