Caenorhabditis elegans O-GlcNAc cycling mutants alter the proteotoxicity of models of human neurodegenerative disorders

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIDDK	NEURO/BEHAV/SENSYS-31

Authors

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

Abstract

O-GlcNAcylation is an important post-translational modification, in which O-GlcNAc can be added onto and removed from serine or threonine residue by two evolutionally conserved enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. O-GlcNAcylation is abundant in the brain and it has been linked to human neurodegenerative disease. We have exploited viable null alleles of the enzymes of O-GlcNAc cycling to examine the role of O-GlcNAcylation in well-characterized C. elegans models of neurodegenerative proteotoxicity. O-GlcNAc cycling dramatically modulated the severity of the proteotoxic phenotype in transgenic models of tauopathy, β-amyloid peptide and polyglutamine expansion. Intriguingly, loss-of-function of OGT alleviated, while loss of OGA enhanced these proteotoxicity phenotype. Consistent with these observations, the O-GlcNAc cycling mutants exhibit altered stress responses and changes in the protein degradation machinery. These findings suggest that modulators of O-GlcNAc cycling may prove useful for anti-neurodegenerative disease therapies. Inspired by the findings in C. elegans, we will further interrogate the role of O-GlcNAc cycling in neurodegeneration in mouse. Brain-specific knock out of OGA has been established for this purpose. Future work will focus on characterizing any pathological changes in the OGA brain KO mice and investigate whether this strain will alter the phenotype of mouse neurodegenerative disease models.

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