title: O-GlcNAc cycling shows neuroprotective potential in C. elegans models of neurodegenerative disease.
abstract: C. elegans has proven to be an excellent organism in which to model human neurodegenerative disease.(1) (-) (7) The worm's simple nervous system, lineage, and neural maps, easily scored movement phenotypes, and robust forward and reverse genetics make it optimal for studying age-dependent processes on a reasonable time scale. A popular approach has been the introduction of transgenes expressing GFP-tagged proteotoxic human proteins into neurons leading to visible aggregation or movement phenotypes.(2) (,) (4) (,) (6) (,) (8) (-) (13) In addition, the maintenance of proteostasis networks has been extensively studied using the power of worm genetics.(8) (-) (13) These networks include genes involved in insulin-like signaling, the heat shock response, the response to hypoxia, and mTOR and AMPK pathways linked to aging.(14) Another pathway with suggestive links to neurodegeneration is the O-GlcNAc cycling pathway, a nutrient-dependent post-translational modification known to be altered in brains from patients with Alzheimer disease.(15) (-) (19) In this commentary, we summarize our recent findings showing that viable mutants of O-GlcNAc cycling in C. elegans dramatically alter the neurotoxicity of four distinct C. elegans models of neurodegenerative disease.(7) Mutants in O-GlcNAc cycling alter the toxicity of mutant tau, polyglutamine expansion reporters, and amyloid β-peptide. The findings further suggest that O-GlcNAc cycling acts at many steps in the lifecycle of aggregation-prone targets. The C. elegans system is likely to continue to provide insights into this complex problem. The involvement of O-GlcNAc cycling in the maintenance of proteostasis raises the possibility of targeting the enzymes catalyzing this critical post-translational modification for therapeutic intervention.
authors.affiliation: NIDDK; NIH; Bethesda, MD USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Hanover
authors.affiliation: NIDDK; NIH; Bethesda, MD USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
keywords: O-GlcNAc; apoptosis; glycobiology; neurodegeneration; proteostasis; signaling; transcription
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