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Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner.

ABSTRACT: 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.

SUBMITTER: Di Nardo A

PROVIDER: S-EPMC2691854 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner.

Di Nardo Alessia A Kramvis Ioannis I Cho Namjik N Sadowski Abbey A Meikle Lynsey L Kwiatkowski David J DJ Sahin Mustafa M

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090501 18

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) st ...[more]

PMID: 19420259

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Project description:UNLABELLED:Hyperactivation of the mechanistic target of rapamycin (mTOR) kinase, as a result of loss-of-function mutations in tuberous sclerosis complex 1 (TSC1) or TSC2 genes, causes protein synthesis dysregulation, increased cell size, and aberrant neuronal connectivity. Dysregulated synthesis of synaptic proteins has been implicated in the pathophysiology of autism spectrum disorder (ASD) associated with TSC and fragile X syndrome. However, cell type-specific translational profiles in these disease models remain to be investigated. Here, we used high-fidelity and unbiased Translating Ribosome Affinity Purification (TRAP) methodology to purify ribosome-associated mRNAs and identified translational alterations in a rat neuronal culture model of TSC. We find that expression of many stress and/or activity-dependent proteins is highly induced while some synaptic proteins are repressed. Importantly, transcripts for the activating transcription factor-3 (Atf3) and mitochondrial uncoupling protein-2 (Ucp2) are highly induced in Tsc2-deficient neurons, as well as in a neuron-specific Tsc1 conditional knock-out mouse model, and show differential responses to the mTOR inhibitor rapamycin. Gelsolin, a known target of Atf3 transcriptional activity, is also upregulated. shRNA-mediated block of Atf3 induction suppresses expression of gelsolin, an actin-severing protein, and rescues spine deficits found in Tsc2-deficient neurons. Together, our data demonstrate that a cell-autonomous program consisting of a stress-induced Atf3-gelsolin cascade affects the change in dendritic spine morphology following mTOR hyperactivation. This previously unidentified molecular cascade could be a therapeutic target for treating mTORopathies. SIGNIFICANCE STATEMENT:Tuberous sclerosis complex (TSC) is a genetic disease associated with epilepsy and autism. Dysregulated protein synthesis has been implicated as a cause of this disease. However, cell type-specific translational profiles that are aberrant in this disease are unknown. Here we show that expression of many stress and/or activity-dependent proteins is highly induced while some synaptic proteins are repressed in neurons missing the Tsc2 gene expression. Identification of genes whose translation is abnormal in TSC may provide insights to previously unidentified therapeutic targets.

Dataset Information

Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner.

Publications

Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner.

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