title: Proteomic Analysis After Status Epilepticus Identifies UCHL1 as Protective Against Hippocampal Injury.
abstract: Brief, non-harmful seizures (preconditioning) can temporarily protect the brain against prolonged, otherwise injurious seizures. Following focal-onset status epilepticus (SE) in preconditioned (tolerance) and sham-preconditioned (injury) mice, we screened for protein changes using a proteomic approach and identified several putative candidates of epileptic tolerance. Among SE-induced changes to both proteomic screens, proteins clustered in key regulatory pathways, including protein trafficking and cytoskeletal regulation. Downregulation of one such protein, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), was unique to injury and not evident in tolerance. UCHL1 inhibition decreased hippocampal ubiquitin, disrupted UPS function, interfered with seizure termination and exacerbated seizure-induced cell death. Though UCHL1 transcription was maintained after SE, we observed downregulation of the pro-translational antisense Uchl1 (AsUchl1) and confirmed that both AsUchl1 and rapamycin can increase UCHL1 expression in vivo. These data indicate that the post-transcriptional loss of UCHL1 following SE is deleterious to neuronal survival and may contribute to hyperexcitability, and are suggestive of a novel modality of rapamycin therapy.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: James P
authors.identifier: http://orcid.org/0000-0002-1086-1424
authors.initials: JP
authors.lastname: Reynolds
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.affiliation: Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Bian
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Mariana
authors.initials: M
authors.lastname: Alves
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Miller-Delaney
authors.affiliation: Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA.
authors.forename: An
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. dhenshall@rcsi.ie.
authors.forename: David C
authors.identifier: http://orcid.org/0000-0001-6237-9632
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism*; D007211:Indoles / Q000008:administration & dosage; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000008:administration & dosage; D040901:Proteomics / Q000379:methods*; D011897:Random Allocation; D013226:Status Epilepticus / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D007211:Indoles; C525086:LDN 57444; D010091:Oximes; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse
keywords: Long non-coding RNA; Proteomics; Temporal lobe epilepsy; UCHL1; Ubiquitin proteasome system