title: Regulation of PERK-eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes.
abstract: Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, including myelin deficits in the CNS; however, underlying mechanisms are not fully understood. TSC1/2 negatively regulate the function of mTOR, which is required for oligodendrocyte differentiation. Here we report that, unexpectedly, constitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death in mice, despite an initial increase of oligodendrocyte precursors during early development. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses by activating a PERK-eIF2α signalling axis and Fas-JNK apoptotic pathways. Enhancement of the phospho-eIF2α adaptation pathway by inhibition of Gadd34-PP1 phosphatase with guanabenz protects oligodendrocytes and partially rescues myelination defects in Tsc1 mutants. Thus, TSC1-mTOR signalling acts as an important checkpoint for maintaining oligodendrocyte homoeostasis, pointing to a previously uncharacterized ER stress mechanism that contributes to hypomyelination in tuberous sclerosis.
authors.affiliation: Key Laboratory of Brain Functional Genomics of STCSM, Institute of Cognitive Neuroscience, East China Normal University, Shanghai 200062, China.|Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
authors.forename: Minqing
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
authors.forename: Xuelian
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lin
authors.affiliation: Key Laboratory of Brain Functional Genomics of STCSM, Institute of Cognitive Neuroscience, East China Normal University, Shanghai 200062, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Sung O
authors.initials: SO
authors.lastname: Yoon
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101, USA.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wood
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.|Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival; D005260:Female; D006143:Guanabenz / Q000494:pharmacology; D006706:Homeostasis; D008297:Male; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D006143:Guanabenz; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D019892:eIF-2 Kinase; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C546843:mTOR protein, mouse; C531557:eIF2alpha kinase, mouse; C513256:Ppp1r15a protein, mouse