Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner.
Tuberous sclerosis complex (TSC) is a neurogenetic disorder caused by loss-of-function mutations in either the TSC1 or TSC2 genes and frequently results in prominent CNS manifestations, including epilepsy, mental retardation, and autism spectrum disorder. The TSC1/TSC2 protein complex plays a major role in controlling the Ser/Thr kinase mammalian target of rapamycin (mTOR), which is a master regulator of protein synthesis and cell growth. In this study, we show that endoplasmic reticulum (ER) stress regulates TSC1/TSC2 complex to limit mTOR activity. In addition, Tsc2-deficient rat hippocampal neurons and brain lysates from a Tsc1-deficient mouse model demonstrate both elevated ER and oxidative stress. In Tsc2-deficient neurons, the expression of stress markers such as CHOP and HO-1 is increased, and this increase is completely reversed by the mTOR inhibitor rapamycin both in vitro and in vivo. Neurons lacking a functional TSC1/TSC2 complex have increased vulnerability to ER stress-induced cell death via the activation of the mitochondrial death pathway. Importantly, knockdown of CHOP reduces oxidative stress and apoptosis in Tsc2-deficient neurons. These observations indicate that ER stress modulates mTOR activity through the TSC protein complex and that ER stress is elevated in cells lacking this complex. They also suggest that some of the neuronal dysfunction and neurocognitive deficits seen in TSC patients may be attributable to ER and oxidative stress and therefore potentially responsive to agents moderating these pathways.
Di Nardo
Alessia
A
The F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kramvis
Ioannis
I
Cho
Namjik
N
Sadowski
Abbey
A
Meikle
Lynsey
L
Kwiatkowski
David J
DJ
Sahin
Mustafa
M
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
D002352:Carrier Proteins; C497250:Ddit3 protein, mouse; D007783:Lactones; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D013912:Threonine; D012694:Serine; C046319:thapsigargicin; D051547:Heme Oxygenase-1; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases