title: Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington's disease.
abstract: In patients with Huntington's disease (HD), the protein huntingtin (Htt) has an expanded polyglutamine (poly-Q) tract. HD results in early loss of medium spiny neurons in the striatum, which impairs motor and cognitive functions. Identifying the physiological role and molecular functions of Htt may yield insight into HD pathogenesis. We found that Htt promotes signaling by mTORC1 [mechanistic target of rapamycin (mTOR) complex 1] and that this signaling is potentiated by poly-Q-expanded Htt. Knocking out Htt in mouse embryonic stem cells or human embryonic kidney cells attenuated amino acid-induced mTORC1 activity, whereas overexpressing wild-type or poly-Q-expanded Htt in striatal neuronal cells increased basal mTOR activity. Striatal cells expressing endogenous poly-Q-expanded Htt showed an increase in the number and size of mTOR puncta on the perinuclear regions compared to cells expressing wild-type Htt. Pull-down experiments indicated that amino acids stimulated the interaction of Htt and the guanosine triphosphatase (GTPase) Rheb (a protein that stimulates mTOR activity), and that Htt forms a ternary complex with Rheb and mTOR. Pharmacologically inhibiting PI3K (phosphatidylinositol 3-kinase) or knocking down Rheb abrogated mTORC1 activity induced by expression of a poly-Q-expanded amino-terminal Htt fragment. Moreover, striatum-specific deletion of TSC1, encoding tuberous sclerosis 1, a negative regulator of mTORC1, accelerated the onset of motor coordination abnormalities and caused premature death in an HD mouse model. Together, our findings demonstrate that mutant Htt contributes to the pathogenesis of HD by enhancing mTORC1 activity.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Pryor
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Biagioli
authors.affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Swarnkar
authors.affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.
authors.forename: Damon T
authors.initials: DT
authors.lastname: Page
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA. ssubrama@scripps.edu.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D048429:Cell Size; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D053208:Kaplan-Meier Estimate; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C490211:RHEB protein, human; D034741:RNA, Small Interfering; D000076205:Ras Homolog Enriched in Brain Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins