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a major protein degradation system that has been associated with several neurodegen- erative disorders and is involved in the regulation of immune cell function. We found increased expression of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits in epileptogenic brain tissue of patients with TSC or FCD, as described in Chapter 4. Glial and neuronal expression of these (immuno)proteasome subunits positively correlated with seizure frequency, suggesting that increased expression of the immunoprotea- some might contribute to seizure activity. In a separate study, we also found increased expression in epileptogenic brain tissue in patients with temporal lobe epilepsy (TLE) and in an experimental model of TLE 30. The immunoproteasome β5i subunit is virtu- ally not expressed in healthy brain, but is strongly induced in epileptogenic brain tissue from patients with drug-resistant epilepsy 31. Recently, it was reported in an experimental model of epilepsy that the β5i subunit is an important contributor in development of seizures and that selective pharmacologic inhibition of this subunit in hippocampal/ento- rhinal cortex slices of rats 2–3 months after brain injury (induced by a status epilepticus) delays or even prevents seizure-like events 32. This suggests that seizures can be reduced or prevented via inhibition of the immunoproteasome. Taken together, these data indi- cate that the increased expression of the β5i subunit in TSC and FCD might contribute to epileptogenesis by promoting seizure development. A very recent study reported that the activity of the ubiquitin-proteasome-system is inhibited in specific hippocampal subregions after status epilepticus in mice, mostly in regions that are more resistant to seizure-induced cell death 33. Also, this study showed that treatment with an proteasome inhibitor protected even the vulnerable CA3 region of the hippocampus against damage 33. The authors suggested that inhibition of the proteasome system might be an endog- enous mechanism to protect against seizure-induced cell death 34. Therefore, additional research is required to study the activation of the (immune)proteasome system in TSC and FCD, and further (pre-)clinical studies are necessary to explore the clinical potential of inhibiting this system. However, specific immunoproteasome inhibitors (e.g. ONX- 0914 32) currently have poor capacities in crossing the blood-brain barrier 35. Hence, the bioavailability of these drugs needs to be improved in order to inhibit the immunoprote- asome system in the epileptogenic brain.
miRNAs in epilepsy
microRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, are crucial modulators of inflammatory pathways linked to various neurological disorders, including epilepsy 36. It is estimated that the expression of approx- imately 60% of all human proteins is directly affected by miRNAs 37. The expression of several miRNAs, including those associated with neuroinflammatory signaling, was pre- viously shown to change in human epileptogenic brain and in experimental models of epilepsy 38-41. Using small RNA sequencing, we found that the miRNA transcriptome was markedly disturbed in TSC cortical tubers, as described in Chapter 3. In accordance with previous studies indicating the importance of the miR34 family in epilepsy 42, 43, we found that miR34a, miR34b and miR34c were strongly upregulated in TSC tubers. miR34b-5p overexpression in mouse hippocampal neurons modulated neurite outgrowth, which indicates that miR34b-5p can potentially regulate aspects of neurogenesis that are altered under pathological conditions and which may contribute to cognitive impair-
DISCUSSION
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