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. 


Authors: Broekaart D.W.M., van Scheppingen J., Geijtenbeek K.W., Zuidberg M.R.J., Anink J.J., Baayen J.C., et al. 

Epilepsia, 2017;58(8):1462-72. 


Objective: Inhibition of the mammalian target of rapamycin (mTOR) pathway reduces epileptogenesis in various epilepsy models, possibly by inhibition of inflammatory processes, which may include the proteasome system. To study the role of mTOR inhibition in the regulation of the proteasome system, we investigated (immuno) proteasome expression during epileptogenesis, as well as the effects of the mTOR inhibitor rapamycin. 

Methods: The expression of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits was investigated during epileptogenesis using immunohistochemistry in the electrical post-status epilepticus (SE) rat model for temporal lobe epilepsy (TLE). The effect of rapamycin was studied on (immuno)proteasome subunit expression in post-SE rats that were treated for 6 weeks. (Immuno)proteasome expression was validated in the brain tissue of patients who had SE or drug-resistant TLE and the effect of rapamycin was studied in primary human astrocyte cultures. 

Results: In post-SE rats, increased (immuno)proteasome expression was detected throughout epileptogenesis in neurons and astrocytes within the hippocampus and piriform cortex and was most evident in rats that developed a progressive form of epilepsy. Rapamycin-treated post-SE rats had reduced (immuno)proteasome protein expression and a lower number of spontaneous seizures compared to vehicle-treated rats. (Immuno)proteasome expression was also increased in neurons and astrocytes within the human hippocampus after SE and in patients with drug-resistant TLE. In vitro studies using cultured human astrocytes showed that interleukin (IL)-1β-induced (immuno)proteasome gene expression could be attenuated by rapamycin. 

Significance: Because dysregulation of the (immuno)proteasome system is observed before the occurence of spontaneous seizures in rats, is associated with progression of epilepsy and can be modulated via the mTOR pathway, it may represent an interesting novel target for drug treatment in epilepsy. 

Authors: Aronica E., Bauer S., Bozzi Y., Caleo M., Dingledine R., Gorter J.A., et al. 

Epilepsia, 2017;58 Suppl 3:27-38


A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. New antiseizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, antiepileptogenesis, and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries. 


Authors: Moavero R., Bombardieri R., Marciano S., Cerminara C., Curatolo P.

J Pediatr Epilepsy, 2016;05(02):064-9


Tuberous sclerosis complex (TSC) is associated with a high rate of epilepsy, which often presents in the first month of life. An early diagnosis of TSC can allow a close electroencephalography monitoring and a prompt detection of subtle or subclinical seizures, thus guaranteeing a prompt treatment. Seizures in TSC are caused by an imbalance between excitation and inhibition, which can be considered as the final step of the genetic mutation and the subsequent overactivation of the mammalian target of rapamycin pathway. Epilepsy is often associated with cognitive and behavioral comorbidities, including learning disability, autism, and attention deficit/hyperactivity disorder. A prompt treatment of early-onset seizures is able to reduce the risk of a subsequent epileptic encephalopathy and cognitive and behavioral sequelae, but it cannot totally revert the final outcome. Treatment options for epilepsy include antiepileptic drugs, epilepsy surgery, ketogenic diet, and vagus nerve stimulation, but even after their application about two-thirds of patients still continue to present seizures. All these treatment options represent symptomatic treatment acting on seizures but not on the underlying cause of epilepsy. Mammalian target of rapamycin inhibitors represent a potential novel treatment strategy able to target the pathophysiologic mechanisms underlying epilepsy and other TSC-related manifestations.

Authors: Switon K., Kotulska K., Janusz-Kaminska A., Zmorzynska J., Jaworski J.

International Union of Biochemistry and Molecular Biology 68:12, 955-962, Dec 2016. 


Tuberous sclerosis complex (TSC) is a rare multi-system disorder, primary manifestations of which are benign tumors and lesions in various organs of the body, including the brain. TSC patients offer suffer from epilepsy, mental retardation, and autism spectrum disorders (ASD). Therefore, TSC serves as a model of epilepsy, ASD, and tumorigenesis. TSC is caused by the lack of function Tsc1-Tsc2 complex, which serves as a major cellular inhibitor of Mammalian Target of Rapamycin Complex 1 (mTORC1). mTORC1 is a kinase controlling most of anabolic processes in eukaryotic cells. Consequently, mTORC1 inhibitors, such as rapaymcin, serve as experimental or already approved drugs for several TSC symptoms. However rapalogs, although quite effective, need to be administered chronically and likely for a lifetime, since therapy discontinuation results in tumor regrowth and epilepsy recurrence. Recent studies revealed that metabolism and excitability (in the case of neurons) of cells lacking Tsc1-Tsc2 complex are changed and these features may potentially be used to treat some of TSC symptoms. In this review, we first provide basic facts about TSC and its molecular background, to next discuss the newest findings in TSC cell biology that can be used to improve existing therapies of TSC and other diseases linked to mTORC1 hyperactivation.