Proteomic Analysis After Status Epilepticus Identifies UCHL1 as Protective Against Hippocampal Injury

• Published in: Neurochemical research Vol. 42; no. 7; pp. 2033 - 2054
• Main Authors: Reynolds, James P., Jimenez-Mateos, Eva M., Cao, Li, Bian, Fang, Alves, Mariana, Miller-Delaney, Suzanne F., Zhou, An, Henshall, David C.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.07.2017; Springer Nature B.V
• Subjects: Animals; Antisense therapy; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain; Cell Biology; Cell death; Cell Survival - drug effects; Cell Survival - physiology; Cytoskeleton; Epilepsy; Hippocampus; Hippocampus - drug effects; Hippocampus - injuries; Hippocampus - metabolism; Hydrolase; Indoles - administration & dosage; Injections, Intraventricular; Injuries; Injury analysis; Male; Mice; Mice, Inbred C57BL; Neurochemistry; Neurology; Neurons - drug effects; Neurons - metabolism; Neurosciences; Original Paper; Oximes - administration & dosage; Post-transcription; Preconditioning; Protein transport; Proteins; Proteomics; Proteomics - methods; Random Allocation; Rapamycin; Rodents; Screens; Seizing; Seizures; Status Epilepticus - drug therapy; Status Epilepticus - genetics; Status Epilepticus - metabolism; Transcription; Ubiquitin; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Temporal lobe epilepsy; UCHL1; Ubiquitin proteasome system; Proteomics; Long non-coding RNA
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-017-2260-6

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 (As Uchl1 ) and confirmed that both As Uchl1 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.