O-GlcNAc modification regulates neurodegenerative proteotoxicity and brain development in C. elegans and mouse models

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIDDK	NEURO/BEHAV/SENSYS-26

Authors

• P. Wang
• B. Lazarus
• M. Forsythe
• M. Comly
• D. Love
• M. Krause
• J. Hanover

Abstract

O-GlcNAcylation on serine or threonine residue by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is an abundant post-translational modification in the brain and has been linked to human neurodegenerative disease. We have exploited viable null alleles of the enzymes of O-GlcNAc modification to examine the role of O-GlcNAcylation in well-characterized C. elegans models of neurodegenerative proteotoxicity. We found that loss-of-function of OGT alleviated, while loss of OGA enhanced the proteotoxic phenotype in transgenic models of tauopathy, β-amyloid peptide and polyglutamine expansion. Consistent with these observations, the O-GlcNAc mutants exhibit altered stress responses and changes in the protein degradation machinery. Inspired by the findings in C. elegans, we further interrogated the role of O-GlcNAcylation in mouse brain. Brain-specific OGA KO mouse showed neurodegenerative phenotype, enlarged ventricles, and metabolic changes. These findings suggest roles for O-GlcNAcylation in neurodegenerative proteotoxicity and brain development and the modulators of O-GlcNAcylation may prove useful for anti-neurodegenerative disease therapies.

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