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Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

ABSTRACT: Reducing mitochondrial electron transport induces a Warburg-like shift to accommodate for the energetic burden caused by brain trauma and salvage dopaminergic neurons. This metabolic shift is evident in the transcriptional upregulation of key genes in the Pyruvate Dehydrogenase Complex and glycolytic pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE173431 | GEO | 2021/08/26

REPOSITORIES: GEO

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Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

Project description:Reducing mitochondrial electron transport induces a Warburg-like shift to accommodate for the energetic burden caused by brain trauma without overwhelming mitochondrial cellular respiration and cellular redox to salvage dopaminergic neurons. This metabolic shift is evident in the transcriptional upregulation of key genes in the Pyruvate Dehydrogenase Complex and glycolytic pathway.

2021-08-26 | GSE179905 | GEO

Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.

Project description:Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

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Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

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Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.

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