Age-related Loss of Neural Stem Cell O-GlcNAc Promotes a Glial Fate Switch Through STAT3 Activation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Aug 28

PMID 32848054

Citations 37

Authors

Charles W White 3rd

Xuelai Fan

Jason C Maynard

Elizabeth G Wheatley

Gregor Bieri

Julien Couthouis

Alma L Burlingame

Saul A Villeda

Affiliations

Soon will be listed here.

Abstract

Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked β--acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the STAT3 signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc-specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of STAT3 O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.

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