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Tuberous Sclerosis Complex Activity Is Required to Control Neuronal Stress Responses in an mTOR-Dependent Manner
Open accessAbstract
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.
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“neurons without a functional TSC1/TSC2 complex have been shown to have increased vulnerability to endoplasmic reticulum stress-induced cell death through the activation of the mitochondrial death pathway [55].”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [55]
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Metadata
- Authors
- Di Nardo, A., Kramvis, I., Cho, N., Sadowski, A., Meikle, L., Kwiatkowski, D. J., & Sahin, M.
- Affiliations
- Boston Children's Hospital (US)
- Brigham and Women's Hospital (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-05-06
- Volume
- 29
- Issue
- 18
- Pages
- 5926-5937
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2691854
- OpenAlex
- W2002327194
- Cited by
- 165
- References
- 69
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 12 · 2020: 6 · 2019: 9 · 2018: 8 · 2017: 10 · 2016: 14 · 2015: 9 · 2014: 10 · 2013: 14 · 2012: 24
- FWCI
- 11.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Tuberous Sclerosis Alliance
- Manton Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS058956, P01NS024279)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- tuberous sclerosis complex, TSC1, TSC2, mTOR, endoplasmic reticulum stress, oxidative stress, neuronal stress response, CHOP, heme oxygenase-1, mitochondrial apoptosis, ER stress-induced cell death, hippocampal neurons, rapamycin, neurocognitive impairment
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Animals, Newborn, Carrier Proteins, Cells, Cultured, Child, Preschool, Dose-Response Relationship, Drug, Embryo, Mammalian, Endoplasmic Reticulum, Flow Cytometry, Gene Expression Regulation, Hippocampus, Humans, Lactones, Male, Mice, Transgenic, Mitochondria, Neurons, Serine, Sesquiterpenes, Threonine, Time Factors, Transduction, Genetic, Tuberous Sclerosis, Tunicamycin, Apoptosis, Reactive Oxygen Species, Phosphotransferases (Alcohol Group Acceptor), Oxidative Stress, Tumor Suppressor Proteins, RNA, Small Interfering, Mice, Heme Oxygenase-1, Transcription Factor CHOP, TOR Serine-Threonine Kinases
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