MassIVE MSV000092637

Partial Public PXD044485

Breakdown of neuronal glycogen protects against tauopathy by reducing oxidative stress

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Description

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. [doi:10.25345/C54T6FD40] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Tauopathy, dietary restriction, glycogen, glycogenolysis, neurodegeneration, oxidative stress, cAMP, therapeutic intervention.

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Principal Investigators:
(in alphabetical order) 		Birgit Schilling, Buck Institute, USA
Lisa Ellerby, Buck Institute for Research on Aging, United States
Pankaj Kapahi, Buck Institute for Research on Aging, United States
Submitting User: jburton1
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