title: Activation of Rheb, but not of mTORC1, impairs spine synapse morphogenesis in tuberous sclerosis complex.
abstract: Mutations in the Tsc1 or Tsc2 genes cause tuberous sclerosis complex (TSC). Tsc1 and Tsc2 proteins form a complex that inhibits mammalian target of rapamycin complex 1 (mTORC1) signalling through Rheb-GTPase. We found that Tsc2(+/-) neurons showed impaired spine synapse formation, which was resistant to an mTORC1 inhibitor. Knockdown of mTOR also failed to restore these abnormalities, suggesting mTORC may not participate in impaired spinogenesis in Tsc2(+/-) neurons. To address whether Rheb activation impairs spine synapse formation, we expressed active and inactive forms of Rheb in WT and Tsc2(+/-) neurons, respectively. Expression of active Rheb abolished dendritic spine formation in WT neurons, whereas inactive Rheb restored spine synapse formation in Tsc2(+/-) neurons. Moreover, inactivation of Rheb with farnesyl transferase inhibitors recovered spine synapse morphogenesis in Tsc2(+/-) neurons. In conclusion, dendritic spine abnormalities in TSC neurons may be caused through activation of Rheb, but not through of mTORC1.
authors.affiliation: 1] Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2].
authors.forename: Shin
authors.initials: S
authors.lastname: Yasuda
authors.affiliation: 1] Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2].
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sugiura
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Shutaro
authors.initials: S
authors.lastname: Katsurabayashi
authors.affiliation: Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Shiga, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Takasaki
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.affiliation: Department of Pathology and Oncology, Juntendo University, School of Medicine, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Pathology and Oncology, Juntendo University, School of Medicine, Tokyo, Japan.
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.affiliation: Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Kanato
authors.initials: K
authors.lastname: Yamagata
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009024:Morphogenesis; D046912:Multiprotein Complexes / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D055647:Rats, Transgenic; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C087693:Rheb protein, rat; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins