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

Autor:	Lane AR; Department of Cell Biology, Emory University, Atlanta, Georgia, USA, 30322., Scher NE; Department of Cell Biology, Emory University, Atlanta, Georgia, USA, 30322., Bhattacharjee S; Neuroscience Institute, Georgia State University, Atlanta, GA 30303., Zlatic SA; Department of Cell Biology, Emory University, Atlanta, Georgia, USA, 30322., Roberts AM; Department of Biochemistry, Emory University, Atlanta, Georgia, USA, 30322.; Department of Neurology, Emory University, Atlanta, Georgia, USA, 30322., Gokhale A; Department of Cell Biology, Emory University, Atlanta, Georgia, USA, 30322., Singleton KS; Department of Cell Biology, Emory University, Atlanta, Georgia, USA, 30322., Duong DM; Department of Biochemistry, Emory University, Atlanta, Georgia, USA, 30322., McKenna M; NanoString Technologies, 530 Fairview Ave N, Seattle, WA 98109., Liu WL; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia, USA, 30322., Baiju A; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia, USA, 30322., Moctezuma FGR; George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332., Tran T; Neuroscience Institute, Georgia State University, Atlanta, GA 30303., Patel AA; Neuroscience Institute, Georgia State University, Atlanta, GA 30303., Clayton LB; Department of Biochemistry & Biophysics and Linus Pauling Institute, Oregon State University, Corvallis, OR 97331., Petris MJ; Departments of Biochemistry, Molecular Microbiology and Immunology, Ophthalmology, and Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211., Wood LB; George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332., Patgiri A; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia, USA, 30322., Vrailas-Mortimer AD; Department of Biochemistry & Biophysics and Linus Pauling Institute, Oregon State University, Corvallis, OR 97331., Cox DN; Neuroscience Institute, Georgia State University, Atlanta, GA 30303., Roberts BR; Department of Biochemistry, Emory University, Atlanta, Georgia, USA, 30322.; Department of Neurology, Emory University, Atlanta, Georgia, USA, 30322., Werner E; Department of Cell Biology, Emory University, Atlanta, Georgia, USA, 30322., Faundez V; Department of Cell Biology, Emory University, Atlanta, Georgia, USA, 30322.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 12. Date of Electronic Publication: 2024 Sep 12.
DOI:	10.1101/2024.09.09.612106
Abstrakt:	Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain and throughout the body, causing seizures and neurodegeneration in infancy. The mechanistic underpinnings of such neuropathology remains unclear. Here, we characterized the molecular mechanisms by which neuronal cells respond to copper depletion in multiple genetic model systems. Targeted deletion of CTR1 in neuroblastoma clonal cell lines produced copper deficiency that was associated with compromised copper-dependent Golgi and mitochondrial enzymes and a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis revealed simultaneous upregulation of mTORC1 and S6K signaling, along with reduced PERK signaling in CTR1 KO cells. 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 as measured by puromycin labeling. These effects of copper depletion were corroborated by spatial transcriptomic profiling of the cerebellum of Atp7a flx/Y :: Vil1 Cre/+ mice, in which copper-deficient Purkinje cells exhibited upregulated protein synthesis machinery and expression of mTORC1-S6K pathway genes. We tested whether increased activity of mTOR in copper-deficient neurons was adaptive or deleterious by genetic epistasis experiments in Drosophila . 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 depletion. Competing Interests: Competing Interest Statement: N/A
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu