title: Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex.
abstract: Rheb is a small GTP-binding protein and its GTPase activity is activated by the complex of Tsc1 and Tsc2 whose mutations cause tuberous sclerosis complex (TSC). We previously reported that cultured TSC neurons showed impaired spine synapse morphogenesis in an mTORC1-independent manner. Here we show that the PDZ protein syntenin preferentially binds to the GDP-bound form of Rheb. The levels of syntenin are significantly higher in TSC neurons than in wild-type neurons because the Rheb-GDP-syntenin complex is prone to proteasomal degradation. Accumulated syntenin in TSC neurons disrupts spine synapse formation through inhibition of the association between syndecan-2 and calcium/calmodulin-dependent serine protein kinase. Instead, syntenin enhances excitatory shaft synapse formation on dendrites by interacting with ephrinB3. Downregulation of syntenin in TSC neurons restores both spine and shaft synapse densities. These findings suggest that Rheb-syntenin signalling may be a novel therapeutic target for abnormalities in spine and shaft synapses in TSC neurons.
authors.affiliation: Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sugiura
authors.affiliation: Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Yasuda
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Shutaro
authors.initials: S
authors.lastname: Katsurabayashi
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawano
authors.affiliation: Center of Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Endo
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Takasaki
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.affiliation: Center of Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Ichikawa
authors.affiliation: Department of Pathology and Oncology, Juntendo University, School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Pathology and Oncology, Juntendo University, School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.affiliation: Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Kanato
authors.initials: K
authors.lastname: Yamagata
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism*; D036389:Ephrin-B3 / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D013569:Synapses / Q000378:metabolism*; D053676:Syntenins / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D036389:Ephrin-B3; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C087693:Rheb protein, rat; D053676:Syntenins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D006153:Guanosine Diphosphate; D020559:Monomeric GTP-Binding Proteins