Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

Abstract

34The molecular mechanisms that shape the gene expression landscape during the development 35 and maintenance of chronic states of brain hyperexcitability are incompletely understood. 36 Here we show that cytoplasmic mRNA polyadenylation, a posttranscriptional mechanism for 37 regulating gene expression, undergoes widespread reorganisation in temporal lobe epilepsy. 38 Specifically, over 25% of the hippocampal transcriptome displayed changes in their poly(A) 39 tail in mouse models of epilepsy, particular evident in the chronic phase. The expression of 40 cytoplasmic polyadenylation binding proteins (CPEB1-4) was found to be altered in the 41 hippocampus in mouse models of epilepsy and temporal lobe epilepsy patients and CPEB4 42 target transcripts were over-represented among those showing poly(A) tail changes. 43 Supporting an adaptive function, CPEB4-deficiency leads to an increase in seizure severity 44 and neurodegeneration in mouse models of epilepsy. Together, these findings reveal an 45 additional layer of gene expression control during epilepsy and point to novel targets for 46 seizure control and disease-modification in epilepsy. 47 48 49 50 51 52 53 54 55 56 57 58 59 Epilepsy is one of the most common chronic neurological disorders, affecting approximately 60 70 million people worldwide 1,2 . Temporal lobe epilepsy (TLE) is the most common 61 refractory form of epilepsy in adults and typically results from an earlier precipitating insult 62 that causes structural and functional reorganisation of neuronal-glial networks within the 63 hippocampus resulting in chronic hyperexcitability 3 . These network changes, which include 64 selective neuronal loss, gliosis and synaptic remodelling, are driven in part by large-scale 65 changes in gene expression 4-7 . The gene expression landscape continues to be dysregulated 66 once epilepsy is established 8 . 67 Recent studies have uncovered important roles for post-transcriptional mechanisms during 68 the development of epilepsy. These include the actions of small noncoding RNA, such as 69 microRNA and post-translational control of protein turnover via the proteasome contributing 70to altered levels of ion channels, changes in neuronal micro-and macro-structure and glial 71 responses within seizure-generating neuronal circuits 9-13 . The molecular mechanisms 72 underlying the transcriptional and translational landscape in epilepsy remain, however, 73 incompletely understood. 74In the cell nucleus, the majority of mRNAs acquire a non-templated poly(A) tail. Although 75 the addition of a poly(A) tail seems to occur by default, the subsequent control of poly(A) tail 76 length is highly regulated both in the nucleus and cytoplasm 14 . Cytoplasmic mRNA 77 polyadenylation contributes to the regulation of the stability, transport and translation of 78 mature transcripts, and is therefore an essential post-transcriptional mechanism for regulating 79 spatio-temporal gene expression 14 . 80The cytoplasmic polyadenylation element binding proteins (CPEBs) are ...