Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.
Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.
Ravikumar
Brinda
B
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
Vacher
Coralie
C
Berger
Zdenek
Z
Davies
Janet E
JE
Luo
Shouqing
S
Oroz
Lourdes G
LG
Scaravilli
Francesco
F
Easton
Douglas F
DF
Duden
Rainer
R
O'Kane
Cahir J
CJ
Rubinsztein
David C
DC
D000818:Animals; D001343:Autophagy; D019556:COS Cells; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; C097188:polyglutamine; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus