title: Decreased O-linked GlcNAcylation protects from cytotoxicity mediated by huntingtin exon1 protein fragment.
abstract: O-GlcNAcylation is an important post-translational modification of proteins and is known to regulate a number of pathways involved in cellular homeostasis. This involves dynamic and reversible modification of serine/threonine residues of different cellular proteins catalyzed by O-linked N-acetylglucosaminyltransferase and O-linked N-acetylglucosaminidase in an antagonistic manner. We report here that decreasing O-GlcNAcylation enhances the viability of neuronal cells expressing polyglutamine-expanded huntingtin exon 1 protein fragment (mHtt). We further show that O-GlcNAcylation regulates the basal autophagic process and that suppression of O-GlcNAcylation significantly increases autophagic flux by enhancing the fusion of autophagosome with lysosome. This regulation considerably reduces toxic mHtt aggregates in eye imaginal discs and partially restores rhabdomere morphology and vision in a fly model for Huntington disease. This study is significant in unraveling O-GlcNAcylation-dependent regulation of an autophagic process in mediating mHtt toxicity. Therefore, targeting the autophagic process through the suppression of O-GlcNAcylation may prove to be an important therapeutic approach in Huntington disease.
authors.affiliation: From the Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016 and.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Pankaj Kumar
authors.initials: PK
authors.lastname: Singh
authors.forename: Rashmi
authors.initials: R
authors.lastname: Parihar
authors.forename: Vibha
authors.initials: V
authors.lastname: Dwivedi
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Lakhotia
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ganesh
mesh_terms: D000215:Acylation; D000818:Animals; D001343:Autophagy; D003603:Cytotoxins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060227:Imaginal Discs / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: D003603:Cytotoxins; D029721:Drosophila Proteins; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins
keywords: Autophagy; Neurodegenerative Diseases; O-GlcNAcylation; Post-translational Modification; Protein Aggregation