title: scyllo-Inositol promotes robust mutant Huntingtin protein degradation.
abstract: Huntington disease is characterized by neuronal aggregates and inclusions containing polyglutamine-expanded huntingtin protein and peptide fragments (polyQ-Htt). We have used an established cell-based assay employing a PC12 cell line overexpressing truncated exon 1 of Htt with a 103-residue polyQ expansion that yields polyQ-Htt aggregates to investigate the fate of polyQ-Htt-drug complexes. scyllo-Inositol is an endogenous inositol stereoisomer known to inhibit accumulation and toxicity of the amyloid-β peptide and α-synuclein. In light of these properties, we investigated the effect of scyllo-inositol on polyQ-Htt accumulation. We show that scyllo-inositol lowered the number of visible polyQ-Htt aggregates and robustly decreased polyQ-Htt protein abundance without concomitant cellular toxicity. We found that scyllo-inositol-induced polyQ-Htt reduction was by rescue of degradation pathways mediated by the lysosome and by the proteasome but not autophagosomes. The rescue of degradation pathways was not a direct result of scyllo-inositol on the lysosome or proteasome but due to scyllo-inositol-induced reduction in mutant polyQ-Htt protein levels.
authors.affiliation: From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Aaron Y
authors.initials: AY
authors.lastname: Lai
authors.forename: Cynthia P
authors.initials: CP
authors.lastname: Lan
authors.forename: Salwa
authors.initials: S
authors.lastname: Hasan
authors.forename: Mary E
authors.initials: ME
authors.lastname: Brown
authors.forename: Joanne
authors.initials: J
authors.lastname: McLaurin
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000071058:Huntingtin Protein; D007294:Inositol / Q000494:pharmacology*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C497606:Snca protein, rat; D051844:alpha-Synuclein; C009217:scyllitol; C097188:polyglutamine; D007294:Inositol; D046988:Proteasome Endopeptidase Complex
keywords: Autophagy; Huntington Disease; Lysosomes; Neurodegenerative Diseases; Proteasome; huntingtin; scyllo-Inositol