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Breakdown of neuronal glycogen protects against tauopathy by reducing oxidative stress

ABSTRACT: The abnormal presence of Microtubule-associated protein Tau (MAPT) has been documented in pathologically linked diseases, including Alzheimer's disease, frontotemporal dementia and other neurodegenerative conditions collectively referred to as tauopathies. We demonstrated that dietary restriction (DR) a robust intervention for lifespan extension and neuroprotection, significantly reduces pathology in a Drosophila melanogaster model of Tauopathy overexpressing a mutant form of human tau. We showed that DR promotes neuroprotection by promoting the breakdown of glycogen. We observed impaired glycogen metabolism in fly and human models of tauopathy, where breakdown of neuronal glycogen occured by activating glycogen phosphorylase (GlyP) reversed Tauopathy phenotypes. Surprisingly, glycogen catabolism in neurons redirects flux to increase the pentose phosphate pathway instead of glycolysis, mitigating oxidative stress. We showed that DR activates GlyP via the cAMP-mediated protein kinase A pathway and pharmacological activation of this pathway mitigated tau pathology, suggesting a potential therapeutic intervention for managing Tauopathy.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Drosophila Melanogaster (ncbitaxon:7227)

SUBMITTER: Pankaj Kapahi Lisa Ellerby Birgit Schilling

PROVIDER: MSV000092637 | MassIVE | Thu Aug 10 11:17:00 BST 2023

SECONDARY ACCESSION(S): PXD044485

REPOSITORIES: MassIVE

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Breakdown of neuronal glycogen protects against tauopathy by reducing oxidative stress

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