PXD059097

PXD059097 is an original dataset announced via ProteomeXchange.

Title	Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration
Description	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 Atp7aflx/Y :: Vil1Cre/+ 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.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_06:28:09.880.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Duc Duong
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-20 06:24:54	ID requested
⏵ 1	2025-05-07 06:28:10	announced

10.1091/mbc.e24-11-0512;

Lane AR, Scher NE, Bhattacharjee S, Zlatic SA, Roberts AM, Gokhale A, Singleton KS, Duong DM, McKenna M, Liu WL, Baiju A, Moctezuma FGR, Tran T, Patel AA, Clayton LB, Petris MJ, Wood LB, Patgiri A, Vrailas-Mortimer AD, Cox DN, Roberts BR, Werner E, Faundez V, Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration. Mol Biol Cell, 36(3):ar33(2025) [pubmed]

submitter keyword: tmt, neurodegeneration, mTOR

Victor Faundez
contact affiliation	Professor Dept. Cell Biology Emory University 615 Michael Street Whitehead 446 Atlanta, GA, 30322
contact email	vfaunde@emory.edu
lab head
Duc Duong
contact affiliation	Center of Neurodegenerative Diseases
contact email	dduong@emory.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD059097
     1. Label: PRIDE project
     2. Name: Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration