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in FCD derived cells. This is in agreement with a recent study showing reduction of the immunoproteasome by rapamycin in H9c2 cells as well as in mouse heart in vivo 62. Evaluation of the possible effect of rapamycin on the expression of the brain immuno- proteasome in vivo deserves further studies and is presently under investigation 63.
Immunoproteasome inhibition as therapeutic strategy?
An example of the possible use of inhibition of the immunoproteasome as therapeutic strategy in epilepsy is represented by the study of Mishto and colleagues 18 in which specific inhibition of the β5i subunit by ONX-0914 64 resulted in prevention, or significant delay, of 4-aminopyridine-induced seizure-like events in acute rat hippocampal/entorhi- nal cortex slices, particularly in slices of epileptic rats. Clinically approved proteasome inhibitors targeting the catalytic activity of both the constitutive proteasome and the immunoproteasome have been already used in hematological malignancies 65-67. New generation small-molecules specifically targeting the immunoproteasome are under clinical development and have been already evaluated in a large variety of animal models of autoimmune diseases and proposed as novel therapeutic approaches for patient with multiple sclerosis, as well as in neurodegenerative diseases (for reviews see 16, 68, 69).
However, recently alternative functions for the immunoproteasome have also been considered, suggesting that the induction of the immunoproteasome may also play a role in neuronal protection and repair after injury, contributing to the preserva- tion of cell viability upon cytokine-induced oxidative stress 49, 70, 71, which is known to be increased within the TSC tubers 72. In particular, evidence has been provided that the immunoproteasome plays a role in the clearance of damaged proteins accumulating upon inflammation or oxidative stress (for review see 49), which are also detected in TSC and FCD 73. Accordingly, formation of aggresome-like induced structures and increased sensitivity to apoptosis has been reported in immunoproteasome-deficiency in cells and in a murine inflammation model 49, 71. Additional studies support alternative physiolog- ical function of the immunoproteasome subunits, including also cell proliferation, cell signaling and synaptic remodeling (for review see 49, 74, 75). Thus an effective therapeutic intervention based on the immunoproteasome has to take into consideration the pres- ervation of the potential beneficial functions of its activation, particularly during brain development.
Concluding remarks
One important question is whether activation of the immunoproteasome system in brain tissue may per se be responsible for an increased susceptibility to seizure activity observed in FCD and TSC. As discussed above, experimental studies in hippocampal/ entorhinal cortex slices suggest the pharmacological inhibition of the β5i subunit may modulate seizure activity. Whether these findings can be translated to other experimen- tal models, including models of FCD and TSC deserves further investigation.
To conclude, our observations support the occurrence of a prominent dereg- ulation of the proteasome system in MCD. In particular the induction of immunopro- teasome subunits in both glial and neuronal cells appear to be a feature of FCD II and TSC and may represent an important accompanying feature of the immune response in these developmental lesions. Therefore, understanding the role of the immunopro-