RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis.
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.
This work was funded in part by support from the Higher Education Authority (HE) Ireland under the “BioAT” PhD scholar programme (to CM). Additional support was from Science Foundation Ireland (08/IN1/B1875, 13/IA/1891 and 14/ADV/RC2721 to DCH) and funding from the European Union Seventh Framework Programme (FP7/2007–2013 to DCH) under grant agreement n° 602130.
CommentsThe original article is available at https://www.nature.com
Published CitationMooney 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
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