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RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis.
Mooney, Claire M; Jimenez-Mateos, Eva M; Engel, Tobias; Mooney, Catherine; Diviney, Mairead; Venø, Morten T; Kjems, Jørgen; Farrell, Michael A; O'Brien, Donncha F; Delanty, Norman; Henshall, David C
<p>The original article is available at https://www.nature.com</p> <p>The nonsense mediated decay (NMD) pathway is a critical surveillance mechanism for identifying aberrant mRNA transcripts. It is unknown, however, whether the NMD system is affected by seizures in vivo and whether changes confer beneficial or maladaptive responses that influence long-term outcomes such the network alterations that produce spontaneous recurrent seizures. Here we explored the responses of the NMD pathway to prolonged seizures (status epilepticus) and investigated the effects of NMD inhibition on epilepsy in mice. Status epilepticus led to increased protein levels of Up-frameshift suppressor 1 homolog (Upf1) within the mouse hippocampus. Upf1 protein levels were also higher in resected hippocampus from patients with intractable temporal lobe epilepsy. Immunoprecipitation of Upf1-bound RNA from the cytoplasmic and synaptosomal compartments followed by RNA sequencing identified unique populations of NMD-associated transcripts and altered levels after status epilepticus, including known substrates such as Arc as well as novel targets including Inhba and Npas4. Finally, long-term video-EEG recordings determined that pharmacologic interference in the NMD pathway after status epilepticus reduced the later occurrence of spontaneous seizures in mice. These findings suggest compartment-specific recruitment and differential loading of transcripts by NMD pathway components may contribute to the process of epileptogenesis.</p>
Keyword(s): Nonsense Mediated mRNA Decay; epilepsy; Physics; Physiology
Publication Date:
2017
Type: Journal article
Peer-Reviewed: Yes
Institution: Royal College of Surgeons in Ireland
Citation(s): Mooney CM, Jimenez-Mateos EM, Engel T, Mooney C, Diviney M, Veno MT, Kjems J, Farrell MA, O'Brien DF, Delanty N, Henshall DC.RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis. Scientific Reports. 2017; 7:41517
Publisher(s): Nature Publishing Group
File Format(s): application/pdf
Related Link(s): https://epubs.rcsi.ie/physiolart/131
First Indexed: 2018-03-18 07:15:07 Last Updated: 2018-03-18 07:15:07