title: Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes.
abstract: Huntington's disease (HD) is caused by a polyglutamine tract expansion in huntingtin (HTT). Despite HTTs ubiquitous expression, there is early and robust vulnerability in striatum, the cause of which is poorly understood. Here, we provide evidence that impaired striatal mTORC1 activity underlies varied metabolic and degenerative phenotypes in HD brain and show that introducing the constitutively active form of the mTORC1 regulator, Rheb, into HD mouse brain, alleviates mitochondrial dysfunction, aberrant cholesterol homeostasis, striatal atrophy, impaired dopamine signaling, and increases autophagy. We also find that the expression of Rhes, a striatum-enriched mTOR activator, is reduced in HD patient and mouse brain and that exogenous addition of Rhes alleviates motor deficits and improves brain pathology in HD mice. Our combined work indicates that impaired Rhes/mTORC1 activity in HD brain may underlie the notable striatal susceptibility and thus presents a promising therapeutic target for HD therapy.
authors.affiliation: Medical Scientist Training Program, Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: The Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Tecedor
authors.affiliation: The Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Yong Hong
authors.initials: YH
authors.lastname: Chen
authors.affiliation: The Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Alex Mas
authors.initials: AM
authors.lastname: Monteys
authors.affiliation: The Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sowada
authors.affiliation: Departments of Psychiatry and Human Behavior, and Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
authors.affiliation: The Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: davidsonbl@email.chop.edu.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
mesh_terms: D000818:Animals; D001284:Atrophy; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D050155:Lipogenesis / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D010641:Phenotype; D000076205:Ras Homolog Enriched in Brain Protein; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse; D020559:Monomeric GTP-Binding Proteins