Proteomics

Dataset Information

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Increased expression of ATase1/NAT8B or ATase2/NAT8 in the mouse results in an autistic-like phenotype with altered dendritic branching and spine formation


ABSTRACT: Neurons heavily depend on the ability of the secretory pathway to deliver correctly folded polypeptides to the periphery of the cell for the assembly, maintenance, and normal functioning of synapses. The endoplasmic reticulum (ER) acetylation machinery has emerged as a novel branch of the more general ER quality control machinery. It regulates the positive selection of correctly folded nascent glycoproteins, thus ensuring the efficiency of the secretory pathway. ER acetylation requires the activity of two ER-luminal acetylCoA:lysine acetyltransferases, ATase1/NAT8B and ATase2/NAT8. Both acetyltransferases depend on the influx of acetyl-CoA into the ER from the cytosol, which is ensued by the coordinated action of the citrate transporters, SLC25A1 and SLC13A5, and the ER acetyl-CoA transporter, AT-1. Gene duplication events affecting ATase1 and ATase2 are associated with rare disease phenotypes that include autism and intellectual disability with dysmorphism. Here, we generated mice with neuron-specific overexpression of human ATase1 or ATase2. The animals display autistic-like behaviors with altered synaptic plasticity, altered neuronal morphology, and altered synaptic structure and function. Mechanistic assessment demonstrates that widespread proteomic changes and altered dynamics of the secretory pathway underly the synaptic defects. The phenotype of ATase1 and ATase2 overexpressing mice is reminiscent of SLC25A1, SLC13A5 and AT-1 overexpressing models. Therefore, our results establish the intracellular citrate/acetyl-CoA pathway, with the ATases acting as the last output, as a metabolic pathway immediately connected to the pathogenesis of certain rare forms of ASD.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Autism Spectrum Disorder

SUBMITTER: Haiyan Lu  

LAB HEAD: Lingjun Li

PROVIDER: PXD051786 | Pride | 2025-07-31

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
Cortex_proteinGroups.txt Txt
Hippo_proteinGroups.txt Txt
Mouse_Crotex_12plex_DiLeu_SCX_HpH_F1_1.raw Raw
Mouse_Crotex_12plex_DiLeu_SCX_HpH_F2_1.raw Raw
Mouse_Crotex_12plex_DiLeu_SCX_HpH_F3_1.raw Raw
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