TY - JOUR
T1 - Raised intracellular glucose concentrations reduce aggredation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy
AU - Ravikumar, Brinda
AU - Stewart, Abigail
AU - Kita, Hiroko
AU - Kato, Kikuya
AU - Duden, Rainer
AU - Rubinsztein, David C.
N1 - Funding Information:
We are grateful to the Commonwealth Scholarship Commission (B.R.), Medical Research Council programme grants to D.C.R. and Steve Brown, and Paul Luzio and Margaret Robinson (A.S.), Hereditary Disease Foundation (D.C.R.) and Japan Science and Technology Corporation (K.K.) for funding. We are grateful for Wellcome Trust Senior Research Fellowships in Clinical Science (D.C.R.) and Basic Biomedical Science (R.D.). We thank Paul Luzio for valuable comments on the manuscript.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0038364056&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddg109
DO - 10.1093/hmg/ddg109
M3 - Scientific review articles
C2 - 12700167
AN - SCOPUS:0038364056
SN - 0964-6906
VL - 12
SP - 985
EP - 994
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 9
ER -