期刊
JOURNAL OF NEUROSCIENCE
卷 35, 期 30, 页码 10762-10772出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4796-14.2015
关键词
autism; dendiritic spines; mTOR; protein synthesis; translation
资金
- John Merck Fund, Nancy Lurie Marks Family Foundation
- National Institutes of Health [P30 HD018655]
- Boston Children's Hospital Translational Research Program
- Manton Center for Orphan Disease Research
- Ruprecht-Karls-University Heidelberg Faculty of Medicine Young Investigator Award Program
- Daimler and Benz Foundation [32-05/13]
- Reinhard-Frank Foundation
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. Dys-regulated 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.
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