title: Dysregulation of the (immuno)proteasome pathway in malformations of cortical development.
abstract: The proteasome is a multisubunit enzyme complex involved in protein degradation, which is essential for many cellular processes. During inflammation, the constitutive subunits are replaced by their inducible counterparts, resulting in the formation of the immunoproteasome.
  
  
  
  We investigated the expression pattern of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits using immunohistochemistry in malformations of cortical development (MCD; focal cortical dysplasia (FCD) IIa and b, cortical tubers from patients with tuberous sclerosis complex (TSC), and mild MCD (mMCD)). Glial cells in culture were used to elucidate the mechanisms regulating immunoproteasome subunit expression.
  
  
  
  Increased expression was observed in both FCD II and TSC; β1, β1i, β5, and β5i were detected (within cytosol and nucleus) in dysmorphic neurons, balloon/giant cells, and reactive astrocytes. Glial and neuronal nuclear expression positively correlated with seizure frequency. Positive correlation was also observed between the glial expression of constitutive and immunoproteasome subunits and IL-1β. Accordingly, the proteasome subunit expression was modulated by IL-1β in human astrocytes in vitro. Expression of both constitutive and immunoproteasome subunits in FCD II-derived astroglial cultures was negatively regulated by treatment with the immunomodulatory drug rapamycin (inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is activated in both TSC and FCD II).
  
  
  
  These observations support the dysregulation of the proteasome system in both FCD and TSC and provide new insights on the mechanism of regulation the (immuno)proteasome in astrocytes and the molecular links between inflammation, mTOR activation, and epilepsy.
authors: Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors: J
authors: J
authors: van Scheppingen
authors: Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors: D W M
authors: DW
authors: Broekaart
authors: Department of Pediatrics, Medical University Vienna, Vienna, Austria.
authors: T
authors: T
authors: Scholl
authors: Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors: M R J
authors: MR
authors: Zuidberg
authors: Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors: J J
authors: JJ
authors: Anink
authors: Department of Pathology, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: W G
authors: WG
authors: Spliet
authors: Department of Neurosurgery, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: P C
authors: PC
authors: van Rijen
authors: Department of Neurosurgery, Medical University Vienna, Vienna, Austria.
authors: T
authors: T
authors: Czech
authors: Department of Pathology, Medical University Vienna, Vienna, Austria.
authors: J A
authors: JA
authors: Hainfellner
authors: Department of Pediatrics, Medical University Vienna, Vienna, Austria.
authors: M
authors: M
authors: Feucht
authors: Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors: A
authors: A
authors: Mühlebner
authors: Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors: E A
authors: EA
authors: van Vliet
authors: Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. e.aronica@amc.uva.nl.|Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands. e.aronica@amc.uva.nl.|Stichting Epilepsie Instellingen Nederland (SEIN), ᅟ, The Netherlands. e.aronica@amc.uva.nl.
authors: E
authors: E
authors: Aronica
mesh_terms: D000293:Adolescent; D000328:Adult; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000002:abnormalities / Q000254:growth & development / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004827:Epilepsy / Q000473:pathology*; D005260:Female; D005333:Fetus; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D054220:Malformations of Cortical Development / Q000473:pathology; D065703:Malformations of Cortical Development, Group I / Q000473:pathology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D014402:Tuberous Sclerosis / Q000473:pathology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex; D020123:Sirolimus
keywords: Astrocytes; Epilepsy; Focal cortical dysplasia; Immunohistochemistry; Immunoproteasome; Inflammation; Tuberous sclerosis complex