Work

Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration

Year: 2025

Type: article

Abstract: Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that was associated with a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 KO cells revealed simultaneous upregulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis. Spatial transcriptomic profiling of Atp7a flx/Y :: Vil1 Cre/+ mice identified upregulated protein synthesis machinery and mTORC1-S6K pathway genes in copper-deficient Purkinje neurons in the cerebellum. Genetic epistasis experiments in Drosophila demonstrated that copper deficiency dendritic phenotypes in class IV neurons are partially rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper deficiency. Significance Copper deficiency is present in rare conditions such as Menkes disease and CTR1 deficiency and in more common diseases like Alzheimer’s. The mechanisms of resilience and ultimate susceptibility to copper deficiency and associated pathology in the brain remain unknown. We demonstrate that in a human cell line, Drosophila , and the mouse cerebellum, copper-deficient neuronal cells exhibit increased protein synthesis through mTORC1 activation and decreased PERK (EIF2AK3) activity. Upregulation of protein synthesis facilitates resilience of neuronal cells to copper deficiency, including partial restoration of dendritic arborization. Our findings offer a new framework for understanding copper deficiency-related pathology in neurological disorders.

Source: Molecular Biology of the Cell

DOI: 10.1091/mbc.e24-11-0512