PMID- 19420259
OWN - NLM
STAT- MEDLINE
DCOM- 20090528
LR  - 20240109
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 29
IP  - 18
DP  - 2009 May 6
TI  - Tuberous sclerosis complex activity is required to control neuronal stress 
      responses in an mTOR-dependent manner.
PG  - 5926-37
LID - 10.1523/JNEUROSCI.0778-09.2009 [doi]
AB  - 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.
FAU - Di Nardo, Alessia
AU  - Di Nardo A
AD  - The F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital 
      Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
FAU - Kramvis, Ioannis
AU  - Kramvis I
FAU - Cho, Namjik
AU  - Cho N
FAU - Sadowski, Abbey
AU  - Sadowski A
FAU - Meikle, Lynsey
AU  - Meikle L
FAU - Kwiatkowski, David J
AU  - Kwiatkowski DJ
FAU - Sahin, Mustafa
AU  - Sahin M
LA  - eng
GR  - P01 NS024279/NS/NINDS NIH HHS/United States
GR  - P30 HD018655/HD/NICHD NIH HHS/United States
GR  - R01 NS058956/NS/NINDS NIH HHS/United States
GR  - R01 NS058956-02/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Carrier Proteins)
RN  - 0 (Ddit3 protein, mouse)
RN  - 0 (Lactones)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sesquiterpenes)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tsc1 protein, rat)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tsc2 protein, rat)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 11089-65-9 (Tunicamycin)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - 67526-94-7 (thapsigargicin)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Apoptosis/drug effects
MH  - Carrier Proteins/*metabolism
MH  - Cells, Cultured
MH  - Child, Preschool
MH  - Dose-Response Relationship, Drug
MH  - Embryo, Mammalian
MH  - Endoplasmic Reticulum/genetics/metabolism
MH  - Flow Cytometry/methods
MH  - Gene Expression Regulation/drug effects/genetics
MH  - Heme Oxygenase-1/metabolism
MH  - Hippocampus/cytology
MH  - Humans
MH  - Lactones/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Mitochondria/drug effects/metabolism
MH  - Neurons/*physiology/ultrastructure
MH  - Oxidative Stress/drug effects/genetics/*physiology
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - RNA, Small Interfering/pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - Serine/metabolism
MH  - Sesquiterpenes/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Threonine/metabolism
MH  - Time Factors
MH  - Transcription Factor CHOP/genetics/metabolism
MH  - Transduction, Genetic/methods
MH  - Tuberous Sclerosis/*metabolism/*pathology
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/deficiency/genetics/metabolism
MH  - Tunicamycin/pharmacology
PMC - PMC2691854
MID - NIHMS115539
EDAT- 2009/05/08 09:00
MHDA- 2009/05/29 09:00
PMCR- 2009/11/06
CRDT- 2009/05/08 09:00
PHST- 2009/05/08 09:00 [entrez]
PHST- 2009/05/08 09:00 [pubmed]
PHST- 2009/05/29 09:00 [medline]
PHST- 2009/11/06 00:00 [pmc-release]
AID - 29/18/5926 [pii]
AID - 3483123 [pii]
AID - 10.1523/JNEUROSCI.0778-09.2009 [doi]
PST - ppublish
SO  - J Neurosci. 2009 May 6;29(18):5926-37. doi: 10.1523/JNEUROSCI.0778-09.2009.