title: Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy.
abstract: Huntington's disease is caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. This gain-of-function mutation is associated with huntingtin aggregation and cell death. Autophagy is an important clearance route for mutant huntingtin exon 1. While mammalian target of rapamycin (mTOR) is a key regulator of autophagy, the upstream modifiers of this process are poorly understood. Our previous expression profiling studies in HD cell models observed changes in four genes associated with glucose metabolism, including the GLUT1 glucose transporter. A role for intracellular glucose as a modulator for polyglutamine toxicity was suggested as cell death was reduced by GLUT1 overexpression. Here we show that the protective effect of GLUT1 is associated with decreased huntingtin exon 1 aggregation in cell models. Consistent with this result, we also observed reduced aggregation and enhanced clearance of mutant huntingtin when cells were cultured in raised glucose concentrations (8 g/l). These effects were mimicked by 8 g/l 2-deoxyglucose (2DOG) (transported, phosphorylated but not metabolized further), but not with 8 g/l 3-O-methyl glucose (transported but not metabolized further). Thus, this phenomenon is probably mediated by glucose-6-phosphate. Increased clearance of mutant huntingtin by raised glucose (8 g/l) and 2DOG correlated with increased autophagy and reduced phosphorylation of mTOR, S6K1 and Akt. Thus, raised intracellular glucose/glucose 6-phosphate levels reduce mutant huntingtin toxicity by increasing autophagy via mTOR and possibly Akt. As mTOR and Akt regulate a diversity of crucial cellular processes, our data also suggest a major new set of targets for intracellular glucose signalling.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Brinda
authors.initials: B
authors.lastname: Ravikumar
authors.forename: Abigail
authors.initials: A
authors.lastname: Stewart
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kita
authors.forename: Kikuya
authors.initials: K
authors.lastname: Kato
authors.forename: Rainer
authors.initials: R
authors.lastname: Duden
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D019556:COS Cells; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D002522:Chlorocebus aethiops; D005947:Glucose / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose