Regulation Of PERK-eIF2α Signaling By Tuberous Sclerosis Complex-1 Controls Homeostasis And Survival Of Mvelinating Oligodendrocytes

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. Patients exhibit cortical tuber, subependymal giant cell astrocytoma and white matter abnormalities. Diffusion tensor imaging studies detected myelin deficits and oligodendrocyte loss in the central nervous system. However, the underlying mechanisms are still not fully understood. Both TSC1 and TSC2 are upstream negative regulators of mammalian-target-of-rapamycin (mTOR) by inhibiting Rheb activity, which is required for oligodendrocyte differentiation. Previous studies demonstrate that mTOR signaling is critical for oligodendrocyte differentiation and myelin formation. However, the underlying mechanism leads to myelin defect and oligodendrocyte loss in TSC patient, as well as whether it is a mTOR activity-dependent process remain unclear.In the current study, we generated a genetic TSC mouse model by using specifically deleting TSC1 gene in the oligodendrocyte precursor cells. We explored the function of TSC1-mTOR pathway in CNS myelination through constitutively activating mTOR signaling and hope to find a potential therapeutic target for hypomyelination in TSC patients.The main body of my thesis major contains three parts, introduction, results and discussion.The introduction focuses on the function of myelin and oligodendrocyte in the central nerve system, as well as the relationship between CNS disease and myelination. Three aspects were discussed respectively, including the regulation mechanisms of oligodendrocyte differentiation, proliferation and apoptosis, the mTOR signaling function in protein synthesis and ER stress response, the hypomyelination in the TSC patient and role of TSC1 in mTOR signaling.Our results show that:1. Unexpectedly, constitutive activation of mTOR signaling caused by Tscl deletion in the oligodendrocyte lineage in mice results in severe myelination defects and oligodendrocyte cell loss, despite an initial increase of oligodendrocyte precursors during early development. Tsc1 ablation elevates OPC proliferating rate in the Tsc1cKO.2. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses through a PERK-eIF2a dependent signaling axis and activates Fas-JNK apoptotic pathways.3. Enhancement of PERK-eIF2a signaling by inhibition of GADD34-PP1 phosphatase with guanabenz protects oligodendrocytes and rescues myelination defects in Tsc1 mutants.The third part is conclusion and discussion. Our studies suggest that TSC1-mTOR signaling acts as an important checkpoint for maintaining oligodendrocyte homeostasis and point to a previously uncharacterized ER stress mechanism that contributes to hypomyelination in TSC disease. The current finding will shed lights on other possible molecular mechanisms underlying TSC and enable us to discovery potential therapeutic targets, i.e, the relationship between the activity threshold of mTOR and oligodendrocyte development and myelination, the involvement of Fas signaling in controlling of OPC apoptosis in the Tscl mutant.