Targeting mRNA polyadenylation as novel treatment strategy in epilepsy
Dr T Engel
Dr J Lucas
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
Epileptogenesis, the process leading to a reduced threshold for seizures after transient brain insults, is associated with large-scale changes in gene expression and processes, such as selective neuronal loss, gliosis and synaptic plasticity which ultimately lead to the formation of seizuregenerating neuronal networks, and the development of epilepsy. Targeting single genes has repeatedly failed to alter the development of epilepsy or reduce the percentage of drug-refractory patients, suggesting approaches which target larger signalling networks may be required. First, however, we must precisely understand which pathological changes contribute to the development of epilepsy and to the maintenance of the epileptic state. Large-scale molecular profiling studies have provided insight into the mechanisms, which may contribute to the formation of aberrant, seizure-generating neuronal circuits, yet we are still far away from a complete picture of the pathological molecular changes occurring during the process of epileptogenesis.
Cytoplasmic polyadenylation is a process by which dormant, translationally inactive mRNA become activated by the elongation of their poly(A) tails. Cytoplasmic polyadenylation element binding proteins (CPEBs1-4) are central factors controlling polyadenylation-induced translation. In the brain, CPEBs mediate numerous cellular processes including long-term potentiation, synaptic plasticity and neurotransmitter receptor expression, processes altered during epileptogenesis. Pilot data produced by the applicant shows, for the first time, that CPEB expression is changed in both experimental models of epilepsy and in drugrefractory epilepsy patient brains suggesting a contribution of CPEBs to seizure-induced pathology. Further, by using mRNA arrays, the applicant has demonstrated mRNA polyadenylation changes affecting up to 20% of the transcriptome during epilepsy. To date, however, neither changes in polyadenylation, nor the contribution of cytoplasmic polyadenylation to disease progression have been studied in the setting of epilepsy.
This highly interdisciplinary PhD project will characterize and decipher an untested layer of gene control contributing to epileptogenesis and provide a new set of therapeutic target genes with a different mechanism of action to better treat patients suffering from epilepsy. By using interdisciplinary approaches (e.g. preclinical mouse models of epilepsy, different transgenic approaches and human-induced stem cells), the student will determine the impact of CPEBs on seizure-induced pathology and the development of epilepsy and identify genes undergoing CPEB-mediated changes in their mRNA polyadenylation status during seizures and epilepsy.