authors: Switon K., Kotulska K., Janusz-Kaminska A., Zmorzynska J., Jaworski J.
Neuroscience 2017 Jan 26;341:112-153.
Mammalian/mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that controls several important aspects of mammalian cell function. mTOR activity is modulated by various intra- and extracellular factors; in turn, mTOR changes rates of translation, transcription, protein degradation, cell signaling, metabolism, and cytoskeleton dynamics. mTOR has been repeatedly shown to participate in neuronal development and the proper functioning of mature neurons. Changes in mTOR activity are often observed in nervous system diseases, including genetic diseases (e.g., tuberous sclerosis complex, Pten-related syndromes, neurofibromatosis, and Fragile X syndrome), epilepsy, brain tumors, and neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, and Huntington's disease). Neuroscientists only recently began deciphering the molecular processes that are downstream of mTOR that participate in proper function of the nervous system. As a result, we are gaining knowledge about the ways in which aberrant changes in mTOR activity lead to various nervous system diseases. In this review, we provide a comprehensive view of mTOR in the nervous system, with a special focus on the neuronal functions of mTOR (e.g., control of translation, transcription, and autophagy) that likely underlie the contribution of mTOR to nervous system diseases.
Authors: D'Gama A.M., Woodworth M.B., Hossain A.A., Bizzotto S., Hatem N.E., LaCoursiere C.M., Naim I., Ying Z., Yang E., Barkovich A.J., Kwiatkowski D., Vinters H.V., Madsen J.R., Mathern G.W., Blümcke I., Poduri A., Walsh C.A.
Cell. Rep. 2017 Dec 26;21(13):3754-3766.
Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the exictatory neuron lineage, causes cortical dysplasia.
Authors: Scheldeman C., Mills J.D., Siekierska A., Serra I., Copmans D., Iyer A.M., et al.
Neurobiol Dis, 2017
Tuberous sclerosis complex (TSC) is a rare, genetic disease caused by loss-of-function mutations in either TSC1 or TSC2. Patients with TSC are neurologically characterized by the presence of abnormal brain structure, intractable epilepsy and TSC-associated neuropsychiatric disorders. Given the lack of effective long-term treatments for TSC, there is a need to gain greater insight into TSC-related pathophysiology and to identify and develop new treatments. In this work we show that homozygous tsc2-/- mutant zebrafish larvae, but nog tsc2+/- and WT larvae display enlarged brains, reduced locomotor behavior and epileptiform discharges at 7 dpf. In addition, we pharmacologically validated the TSC model by demonstrating the dramatic rescue effect of pericardially injected rapamycin, a well-known mTOR inhibitor, on selected behavioral read-outs and at the molecular level. By means of transcriptome profiling we also acquired more insight into the neuropathology of TSC, and as a result were able to highight possible new treatment targets. The gene expression profiles of WT and tsc2+/- larvae revealed 117 differentially expressed genes (DEGs), while between WT and tsc2-/- larvae and tsc2+/- and tsc2-/- larvae there were 1414 and 1079 DEGs, respectively. Pathway enrichment analysis from the WT and tsc2-/- DEGs, identified 14 enriched pathways from the up-regulated genes and 6 enriched pathways from the down-regulated genes. Moreover, genes related to inflammation and immune response were up-regulated in the heads of tsc2-/- larvae, in line with the findings in human brain tissue where inflammatory and immune responses appear to be major hallmarks of TSC. Taken together, our phenotypic, transcriptomic and pharmacological analysis identified the tsc2-/- zebrafish as a preclinical model that mirrors well aspects of the human condition and delineated relevant TSC-related biological pathways. The model may be of value for future TSC-related drug discovery and development programs.
Authors: Moavero R., Carai A., Mastronuzzi A., Marciano S., Graziola F., Vigevano F., et al.
Pediatric Neurology, 2017;68:59-63
Background: Subependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus.
Methods: We collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell astrocytomas and who could not undergo surgery for different reasons.
Results: All patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals.
Conclusions: Our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk.
Authors: Mills J.D., Iyer A.M., van Scheppingen J., Bongaarts A., Anink J.J., Janssen B. et al.
Scientific reports, 2017;7(1):8089
Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provied new insights into the TSC transcriptomic network along with the identification of potential new treatment targets.