title: Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury.
abstract: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability thresholds that are altered by epileptogenic insults. Dysfunction of the UPS has been reported to occur in a brain region- and cell-specific manner and contribute to disease progression in acute and chronic brain diseases. Prolonged seizures, status epilepticus, may alter UPS function but there has been no systematic attempt to map when and where this occurs in vivo or to determine the consequences of proteasome inhibition on seizure-induced brain injury.
  
  
  
  To determine whether seizures lead to an impairment of the UPS, we used a mouse model of status epilepticus whereby seizures are triggered by an intra-amygdala injection of kainic acid. Status epilepticus in this model causes cell death in selected brain areas, in particular the ipsilateral CA3 subfield of the hippocampus, and the development of epilepsy after a short latent period. To monitor seizure-induced dysfunction of the UPS we used a UPS inhibition reporter mouse expressing the ubiquitin fusion degradation substrate ubiquitinG76V-green fluorescent protein. Treatment with the specific proteasome inhibitor epoxomicin was used to establish the impact of proteasome inhibition on seizure-induced pathology.
  
  
  
  Our studies show that status epilepticus induced by intra-amygdala kainic acid causes select spatio-temporal UPS inhibition which is most evident in damage-resistant regions of the hippocampus, including CA1 pyramidal and dentate granule neurons then appears later in astrocytes. In support of this exerting a beneficial effect, injection of mice with the proteasome inhibitor epoxomicin protected the normally vulnerable hippocampal CA3 subfield from seizure-induced neuronal death in the model. These studies reveal brain region- and cell-specific UPS impairment occurs after seizures and suggest UPS inhibition can protect against seizure-induced brain damage. Identifying networks or pathways regulated through the proteasome after seizures may yield novel target genes for the treatment of seizure-induced cell death and possibly epilepsy.
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland. tengel@rcsi.ie.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: Jaime
authors.initials: J
authors.lastname: Martinez-Villarreal
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.|Medical Clinic III, University Clinic Dresden, TU Dresden, Dresden, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Henke
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: Amaya
authors.initials: A
authors.lastname: Sanz-Rodriguez
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: Mariana
authors.initials: M
authors.lastname: Alves
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Hernandez-Santana
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Brennan
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: Aidan
authors.initials: A
authors.lastname: Kenny
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: Aoife
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Lucas
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 111 St. Stephen's Green, Dublin, 02 YN77, Ireland.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D013226:Status Epilepticus / Q000503:physiopathology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: Epilepsy; Epileptogenesis; Hippocampal sclerosis; Neuroprotection; Proteasome inhibition; Status epilepticus; Ubiquitin-proteasome system