Reynolds, JP; Jimenez-Mateos, EM; Cao, L; Bian, F; Alves, M; Miller-Delaney, SF; Zhou, A; Reynolds, JP; Jimenez-Mateos, EM; Cao, L; Bian, F; Alves, M; Miller-Delaney, SF; Zhou, A; Henshall, DC; - view fewer (2017) Proteomic Analysis After Status Epilepticus Identifies UCHL1 as Protective Against Hippocampal Injury. Neurochemical Research , 42 pp. 2033-2054. 10.1007/s11064-017-2260-6.

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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.

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