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Nutrient-driven O-GlcNAc cycling influences autophagic flux and neurodegenerative proteotoxicity

Peng Wang1, John A Hanover

  • 1Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Autophagy
|January 19, 2013
PubMed

Insights

O-GlcNAc cycling regulates neurodegeneration by impacting insulin signaling and autophagy. Modulating O-GlcNAc transferase (OGT) and O-GlcNAc selective β-N-acetyl-D-glucosaminidase (OGA) affects proteotoxicity in C. elegans models.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • O-GlcNAcylation is a post-translational modification linked to neurodegenerative diseases.
  • The enzymes O-GlcNAc transferase (OGT) and O-GlcNAc selective β-N-acetyl-D-glucosaminidase (OGA) control O-GlcNAcylation levels.

Purpose of the Study:

  • To investigate the role of O-GlcNAc cycling in C. elegans models of neurodegeneration.
  • To determine how OGT and OGA influence proteotoxicity and cellular pathways.

Main Methods:

  • Utilized C. elegans models of tauopathy, β-amyloid peptide, and polyglutamine expansion.
  • Analyzed the impact of OGT and OGA loss-of-function on proteotoxicity.
  • Assessed changes in insulin signaling, proteasome activity, and autophagy markers (GFP::LGG-1).

Main Results:

  • Loss of OGT alleviated, while loss of OGA enhanced, proteotoxicity in neurodegenerative models.
  • O-GlcNAc cycling mutants exhibited altered insulin signaling, proteasome activity, and autophagy.
  • Accumulation of GFP::LGG-1 and PE-modified GFP::LGG-1 was observed in mutants lacking OGT or OGA, particularly under starvation.

Conclusions:

  • O-GlcNAc cycling is a critical regulator of neurodegenerative disease progression in C. elegans.
  • O-GlcNAc cycling impacts key cellular processes including insulin signaling and autophagy.
  • O-GlcNAc cycling may regulate autophagic flux through direct modification of BECN1 and BCL2.
Keywords:
O-GlcNAcautophagyinsulin signalingneurodegenerationproteasomeproteostasisproteotoxicity

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