title: mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis.
abstract: Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD), including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2(+/-) and TSC2(-/-) neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: veronica.costa@roche.com.
authors.forename: Veronica
authors.initials: V
authors.lastname: Costa
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aigner
authors.affiliation: Department of Biomedicine, University of Basel, Pestalozzistrasse 20, 4056 Basel, Switzerland.
authors.forename: Mirko
authors.initials: M
authors.lastname: Vukcevic
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Sauter
authors.affiliation: Department of Biomedicine, University of Basel, Pestalozzistrasse 20, 4056 Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Behr
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Tom
authors.initials: T
authors.lastname: Dunkley
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Arno
authors.initials: A
authors.lastname: Friedlein
authors.affiliation: Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Sannah
authors.initials: S
authors.lastname: Zoffmann
authors.affiliation: Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Claas A
authors.initials: CA
authors.lastname: Meyer
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Knoflach
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lugert
authors.affiliation: Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Patsch
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Fjeldskaar
authors.affiliation: Department of Neurosurgery, Universitätsspital Basel, ZLF 20 Hebelstrasse, 4031 Basel, Switzerland.
authors.forename: Laurie
authors.initials: L
authors.lastname: Chicha-Gaudimier
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kiialainen
authors.affiliation: Pvalue Research SRL, 29015 Castel San Giovanni, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piraino
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Bedoucha
authors.affiliation: Roche Pharmaceutical Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Graf
authors.affiliation: Brain Research Institute, Faculty of Medicine and Science, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jessberger
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Anirvan
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Biomedicine, University of Basel, Pestalozzistrasse 20, 4056 Basel, Switzerland.
authors.forename: Josef
authors.initials: J
authors.lastname: Bischofberger
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience Ophthalmology and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: ravi.jagasia@roche.com.
authors.forename: Ravi
authors.initials: R
authors.lastname: Jagasia
mesh_terms: D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D055495:Neurogenesis; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: autism spectrum disorder; human pluripotent stem cells; mTORC1; neuronal differentiation; synaptogenesis; tuberous sclerosis