title: The immunoproteasome β5i subunit is a key contributor to ictogenesis in a rat model of chronic epilepsy.
abstract: The proteasome is the core of the ubiquitin-proteasome system and is involved in synaptic protein metabolism. The incorporation of three inducible immuno-subunits into the proteasome results in the generation of the so-called immunoproteasome, which is endowed of pathophysiological functions related to immunity and inflammation. In healthy human brain, the expression of the key catalytic β5i subunit of the immunoproteasome is almost absent, while it is induced in the epileptogenic foci surgically resected from patients with pharmaco-resistant seizures, including temporal lobe epilepsy. We show here that the β5i immuno-subunit is induced in experimental epilepsy, and its selective pharmacological inhibition significantly prevents, or delays, 4-aminopyridine-induced seizure-like events in acute rat hippocampal/entorhinal cortex slices. These effects are stronger in slices from epileptic vs normal rats, likely due to the more prominent β5i subunit expression in neurons and glia cells of diseased tissue. β5i subunit is transcriptionally induced in epileptogenic tissue likely by Toll-like receptor 4 signaling activation, and independently on promoter methylation. The recent availability of selective β5i subunit inhibitors opens up novel therapeutic opportunities for seizure inhibition in drug-resistant epilepsies.
authors.affiliation: Institut für Biochemie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Centro Interdipartimentale di Ricerca sul Cancro "Giorgio Prodi", Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy. Electronic address: michele.mishto@charite.de.
authors.forename: Michele
authors.initials: M
authors.lastname: Mishto
authors.affiliation: Institut für Neurophysiology, Charité - Universitätsmedizin Berlin, Garystr. 5, 14195 Berlin, Germany.
authors.forename: Muhammad L
authors.initials: ML
authors.lastname: Raza
authors.affiliation: Dept. of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Via S. Giacomo 12, 40126 Bologna, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: de Biase
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via Giuseppe La Masa 19, 20156 Milan, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ravizza
authors.affiliation: Institute of Oncology and Transplant Pathology at Department of Experimental, Diagnostic and Specialty Medicine, DIMES, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vasuri
authors.affiliation: Dept. of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Via S. Giacomo 12, 40126 Bologna, Italy.
authors.forename: Morena
authors.initials: M
authors.lastname: Martucci
authors.affiliation: Institut für Biochemie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Keller
authors.affiliation: Dept. of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum, University of Bologna, Via S. Giacomo 12, 40126 Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bellavista
authors.affiliation: Onyx Pharmaceuticals Inc., Amgen Subsidiary, 249 E. Grand Ave., South San Francisco, CA 94080, USA.
authors.forename: Tonia J
authors.initials: TJ
authors.lastname: Buchholz
authors.affiliation: Institut für Biochemie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kloetzel
authors.affiliation: Department of Pharmacy and Biotechnology, FaBiT, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pession
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via Giuseppe La Masa 19, 20156 Milan, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.affiliation: Institut für Neurophysiology, Charité - Universitätsmedizin Berlin, Garystr. 5, 14195 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000503:physiopathology; D004827:Epilepsy / Q000201:enzymology* / Q000503:physiopathology; D006624:Hippocampus / Q000503:physiopathology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D012333:RNA, Messenger; D046988:Proteasome Endopeptidase Complex
keywords: Neuroinflammation; Pharmaco-resistant seizures; Pilocarpine; Proteasome inhibitors