title: Induction of autophagy with catalytic mTOR inhibitors reduces huntingtin aggregates in a neuronal cell model.
abstract: Huntington's disease is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. This expansion produces a mutant form of the huntingtin protein, which contains an elongated polyglutamine stretch at its amino-terminus. Mutant huntingtin may adopt an aberrant, aggregation-prone conformation predicted to start the pathogenic process leading to neuronal dysfunction and cell death. Thus, strategies reducing mutant huntingtin may lead to disease-modifying therapies. We investigated the mechanisms and molecular targets regulating huntingtin degradation in a neuronal cell model. We first found that mutant and wild-type huntingtin displayed strikingly diverse turn-over kinetics and sensitivity to proteasome inhibition. Then, we show that autophagy induction led to accelerate degradation of mutant huntingtin aggregates. In our neuronal cell model, allosteric inhibition of mTORC1 by everolimus, a rapamycin analogue, did not induce autophagy or affect aggregate degradation. In contrast, this occurred in the presence of catalytic inhibitors of both mTOR complexes mTORC1 and mTORC2. Our data demonstrate the existence of an mTOR-dependent but everolimus-independent mechanism regulating autophagy and huntingtin-aggregate degradation in cells of neuronal origin.
authors.affiliation: Novartis Institutes for BioMedical Research, Neuroscience Discovery, Basel, Switzerland.
authors.forename: Ana
authors.initials: A
authors.lastname: Roscic
authors.forename: Barbara
authors.initials: B
authors.lastname: Baldo
authors.forename: Christophe
authors.initials: C
authors.lastname: Crochemore
authors.forename: David
authors.initials: D
authors.lastname: Marcellin
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D000068338:Everolimus; D005091:Exons / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D007118:Immunoassay; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007700:Kinetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D008959:Models, Neurological; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D000068338:Everolimus; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus