Dataset Information

Oligodendrocyte precursor cell-specific blocking of low glucose-induced activation of AMPK ensures myelination and remyelination

ABSTRACT: In this study, we screening the main types of cerebral cortex cells for glucose sensing and have find that AMPK is not activated in OPCs. We further discover that aldolase C (ALDOC) is acetylated at K14 in OPCs. Expression of ALDOC-K14R, with the acetylation lysine residues changed to arginine, renders OPCs able to activate AMPK in response to low glucose, and suppresses myelin regeneration in cuprizone, Lysolecithin (LPC) and EAE-induced demyelination model. But, genetic depletion of AMPKα1 and AMPKα2 in OPCs prevents the impact of ALDOC-K14R in remyelination. Furthermore, when OPCs activing AMPK with the TRPV antagonist AMG9810 or the hAMPKγ1D317A mutant, the proliferation and differentiation are both inhibited. Thus, our study reveals that ALDOC acetylation in OPCs plays a key role to prevent AMPK activation to endure its myelin repair function in neuronal disorders.

ORGANISM(S): Rattus Rattus Homo Sapiens

SUBMITTER: Chensong Zhang

PROVIDER: PXD067336 | iProX | Wed Aug 13 00:00:00 BST 2025

REPOSITORIES: iProX

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Oligodendrocyte precursor cell-specific blocking of low-glucose-induced activation of AMPK ensures myelination and remyelination.

Sun Yuxia Y Zhang Wei-Wei WW Men Lu L Wu Jianfeng J Yao Luming L Huang Xi X Wu Yaying Y Zhang Cixiong C Chen Ying Y Carling David D Zhang Chen-Song CS Lin Sheng-Cai SC

Nature metabolism 20251022 11

It has been shown that in most cells, low glucose leads to activation of AMP-activated protein kinase (AMPK) via the lysosomal glucose-sensing pathway, where glycolytic aldolase acts as the glucose sensor. Here, we show that ALDOC (aldolase C), the predominant isozyme of aldolase in mouse and rat oligodendrocyte precursor cells (OPCs), is acetylated at lysine 14, making the lysosomal glucose-sensing AMPK pathway unable to operate. We find that the blockage of AMPK activation is required for the ...[more]

PMID: 41125938

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Project description:The yeast Saccharomyces cerevisiae thrives in sugar-rich environments by rapidly consuming glucose and favoring alcoholic fermentation. This strategy is tightly regulated by the glucose repression pathway, which prevents the expression of genes required for the utilization of alternative carbon source. Central to this regulatory network is the yeast ortholog of the heterotrimeric 5′AMP-activated protein kinase (AMPK), which adjusts gene expression in response to glucose availability. The activity of the yeast AMPK complex is primarily regulated by the phosphorylation state of its catalytic subunit Snf1, a process orchestrated by a balance between upstream kinases and phosphatases. Among the latter, the Protein Phosphatase 1 (PP1) complex Reg1/Glc7 plays a critical role in inhibiting Snf1 activity under glucose-rich conditions. Despite its importance, the precise mechanism by which glucose availability leads to Snf1 inhibition remains incompletely understood. Evidence suggests that hexokinase 2 (Hxk2) participates in this pathway, potentially coupling the early steps of glucose metabolism to Snf1 signaling. Notably, the toxic glucose analog 2-deoxyglucose (2DG)- which is phosphorylated by Hxk2 but not further metabolized- mimics glucose in its ability to repress Snf1, implicating glucose or 2DG phosphorylation as a key regulatory signal. Additionally, yeast AMPK activity correlates with 2DG resistance through mechanisms that are incompletely described. In this study, we performed a large-scale 2DG-resistance genetic screen to explore both the molecular basis of 2DG resistance and AMPK regulation in yeast. The identified mutations confer resistance either by reducing 2DG phosphorylation (e.g., mutations in HXK2) or by enhancing constitutive Snf1 activity, via gain-of-function alleles in AMPK subunits or loss-of-function mutations in REG1 and GLC7. We also describe a novel series of REG1 missense mutations, including reg1-W165G, that maintain basal, glucose-regulated Snf1 activity but fail to mediate 2DG-induced Snf1 inhibition. These findings position Reg1 as a central mediator in glucose sensing, possibly by sensing 2DG-derived -and by extension, glucose-derived- metabolites.

Dataset Information

Oligodendrocyte precursor cell-specific blocking of low glucose-induced activation of AMPK ensures myelination and remyelination

Publications

Oligodendrocyte precursor cell-specific blocking of low-glucose-induced activation of AMPK ensures myelination and remyelination.

Similar Datasets

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