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Regulation of PERK-eIF2α Signaling by Tuberous Sclerosis Complex-1 Controls Homeostasis and Survival of Myelinating Oligodendrocytes

ABSTRACT: Tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by mutations in either TSC1 or TSC2, exhibits white matter abnormalities including CNS myelin deficits. however, underlying mechanisms are not fully understood. Here we find that, unexpectedly, constitutive activation of mTOR signaling caused by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses through the PERK‐eIF2α dependent signaling axis and activates Fas-JNK apoptotic pathways. Our studies suggest that TSC1-mTOR signaling acts as an important checkpoint for maintaining oligodendrocyte homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE74893 | GEO | 2016/07/22

SECONDARY ACCESSION(S): PRJNA301738

REPOSITORIES: GEO

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Regulation of PERK-eIF2Î± Signaling by Tuberous Sclerosis Complex-1 Controls Homeostasis and Survival of Myelinating Oligodendrocytes

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Project description:Tuberous sclerosis complex (TSC) is a rare genetic disease caused by abnormal of TSC1 or TSC2 gene. Our previous data deduced that IQGAP2 can be one of the genes potentially responsible for non-TSC1 or TSC2 mutation TSC patients. To investigate the pathogenesis of IQGAP2 in TSC, we performed global transcriptome, proteome, and phosphoproteome analyses and found the alter of genes related to mTOR signaling pathway in IQGAP2 knockdown cells. In addition, we found that knockdown of IQGAP2 resulted in increased cell proliferation and enhanced the phosphorylation level of AKT and S6K by functional analysis, meanwhile, the AKT and mTOR inhibitors can partially rescue cell abnormal proliferation by decreasing hyperphosphorylation. Our data revealed a potential connection between mTOR signaling pathway and aberrant cell proliferation in IQGAP2 knockdown cells, and provide a new latent therapeutic strategy for non-TSC1 or TSC2 mutation patients.

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