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Author (up) Costa, V.; Aigner, S.; Vukcevic, M.; Sauter, E.; Behr, K.; Ebeling, M.; Dunkley, T.; Friedlein, A.; Zoffmann, S.; Meyer, C.A.; Knoflach, F.; Lugert, S.; Patsch, C.; Fjeldskaar, F.; Chicha-Gaudimier, L.; Kiialainen, A.; Piraino, P.; Bedoucha, M.; Graf, M.; Jessberger, S.; Ghosh, A.; Bischofberger, J.; Jagasia, R.
Title mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis Type Journal Article
Year 2016 Publication Cell Reports Abbreviated Journal Cell Rep
Volume 15 Issue 1 Pages 86-95
Keywords Cell Line; Embryonic Stem Cells/cytology/metabolism; Humans; Multiprotein Complexes/*antagonists & inhibitors/metabolism; Neural Stem Cells/cytology/*metabolism/physiology; *Neurogenesis; Synapses/*metabolism/physiology; Synaptic Transmission; TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism; Tuberous Sclerosis/genetics/*metabolism; Tumor Suppressor Proteins/genetics; autism spectrum disorder; human pluripotent stem cells; mTORC1; neuronal differentiation; synaptogenesis; 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.
Address 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
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 2211-1247 ISBN Medium
Area Expedition Conference
Notes PMID:27052171 Approved no
Call Number refbase @ user @ Serial 16690
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Author (up) Crawford, K.; Calo, R.
Title There is a blind spot in AI research Type Journal Article
Year 2016 Publication Nature Abbreviated Journal
Volume 538 Issue 7625 Pages 311-313
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Address
Corporate Author Thesis
Publisher Springer Nature Place of Publication Editor
Language Summary Language Original Title
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ISSN ISBN Medium
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Notes Approved no
Call Number refbase @ admin @ crawford_there_2016 Serial 17426
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Author (up) Dametti, S.; Faravelli, I.; Ruggieri, M.; Ramirez, A.; Nizzardo, M.; Corti, S.
Title Experimental Advances Towards Neural Regeneration from Induced Stem Cells to Direct In Vivo Reprogramming Type Journal Article
Year 2016 Publication Molecular Neurobiology Abbreviated Journal Mol Neurobiol
Volume 53 Issue 4 Pages 2124-2131
Keywords Animals; *Cellular Reprogramming; Humans; Induced Pluripotent Stem Cells/*cytology; *Nerve Regeneration; Neural Stem Cells/cytology; In vivo reprogramming; Neural stem cells; Neuronal loss; Regeneration
Abstract Neuronal loss is a common substrate of many neurological diseases that still lack effective treatments and highly burden lives of affected individuals. The discovery of self-renewing stem cells within the central nervous system (CNS) has opened the doors to the possibility of using the plasticity of CNS as a potential strategy for the development of regenerative therapies after injuries. The role of neural progenitor cells appears to be crucial, but insufficient in reparative processes after damage. In addition, the mechanisms that regulate these events are still largely unknown. Stem cell-based therapeutic approaches have primarily focused on the use of either induced pluripotent stem cells or induced neural stem cells as sources for cell transplantation. More recently, in vivo direct reprogramming of endogenous CNS cells into multipotent neural stem/progenitor cells has been proposed as an alternative strategy that could overcome the limits connected with both the invasiveness of exogenous cell transplantation and the technical issues of in vitro reprogramming (i.e., the time requested and the limited available amount of directly induced neuronal cells). In this review, we aim to highlight the recent studies on in vivo direct reprogramming, focusing on astrocytes conversion to neurons or to neural stem/precursors cells, in the perspective of future therapeutic purposes for neurological disorders.
Address Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy. stefania.corti@unimi.it
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0893-7648 ISBN Medium
Area Expedition Conference
Notes PMID:25934102 Approved no
Call Number refbase @ user @ Serial 16766
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Author (up) Dandulakis, M.G.; Meganathan, K.; Kroll, K.L.; Bonni, A.; Constantino, J.N.
Title Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research Type Journal Article
Year 2016 Publication Journal of Neurodevelopmental Disorders Abbreviated Journal J Neurodev Disord
Volume 8 Issue Pages 22
Keywords Asd; Autism; Developmental disorders; X chromosome; X-inactivation; X-linked ASD; X-reactivation; iPSC; “Female protective effect”
Abstract Induced pluripotent stem cells (iPSCs) allow researchers to make customized patient-derived cell lines by reprogramming noninvasively retrieved somatic cells. These cell lines have the potential to faithfully represent an individual's genetic background; therefore, in the absence of available human brain tissue from a living patient, these models have a significant advantage relative to other models of neurodevelopmental disease. When using human induced pluripotent stem cells (hiPSCs) to model X-linked developmental disorders or inherited conditions that undergo sex-specific modulation of penetrance (e.g., autism spectrum disorders), there are significant complexities in the course and status of X chromosome inactivation (XCI) that are crucial to consider in establishing the validity of cellular models. There are major gaps and inconsistencies in the existing literature regarding XCI status during the derivation and maintenance of hiPSCs and their differentiation into neurons. Here, we briefly describe the importance of the problem, review the findings and inconsistencies of the existing literature, delineate options for specifying XCI status in clonal populations, and develop recommendations for future studies.
Address Department of Psychiatry, Washington University in St. Louis, Campus Box 8134, 660 S. Euclid Avenue, St. Louis, MO 63110 USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1866-1947 ISBN Medium
Area Expedition Conference
Notes PMID:27303449; PMCID:PMC4907282 Approved no
Call Number refbase @ user @ Serial 16674
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Author (up) Darville, H.; Poulet, A.; Rodet-Amsellem, F.; Chatrousse, L.; Pernelle, J.; Boissart, C.; Heron, D.; Nava, C.; Perrier, A.; Jarrige, M.; Coge, F.; Millan, M.J.; Bourgeron, T.; Peschanski, M.; Delorme, R.; Benchoua, A.
Title Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome Type Journal Article
Year 2016 Publication EBioMedicine Abbreviated Journal EBioMedicine
Volume 9 Issue Pages 293-305
Keywords Autism; Drug repurposing; High throughput screening; Lithium; Shank3; Valproate
Abstract Autism spectrum disorders affect millions of individuals worldwide, but their heterogeneity complicates therapeutic intervention that is essentially symptomatic. A versatile yet relevant model to rationally screen among hundreds of therapeutic options would help improving clinical practice. Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using SHANK3 haploinsufficiency as a proof of principle. A library of compounds was screened for potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells. Using induced pluripotent stem cell technology, active compounds were then evaluated for efficacy in correcting dysfunctional networks of neurons differentiated from individuals with deleterious point mutations of SHANK3. Among 202 compounds tested, lithium and valproic acid showed the best efficacy at corrected SHANK3 haploinsufficiency associated phenotypes in cellulo. Lithium pharmacotherapy was subsequently provided to one patient and, after one year, an encouraging decrease in autism severity was observed. This demonstrated that pluripotent stem cell-derived neurons provide a novel cellular paradigm exploitable in the search for specific disease-modifying treatments.
Address CECS, I-STEM, AFM, 91030 Evry Cedex, France. Electronic address: abenchoua@istem.fr
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 2352-3964 ISBN Medium
Area Expedition Conference
Notes PMID:27333044; PMCID:PMC4972535 Approved no
Call Number refbase @ user @ Serial 16673
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