Aberrant transcriptional networks in human epileptic tissue

Coordinator:		Prof. Dr. Albert Becker
Institution:		Institut für Neuropathologie, Bonn
Homepage:		http://www.meb.uni-bonn.de/neuropath/

Epilepsy and migraine are complex disorders of the central nervous system. Both diseases have in common episodically increased neuronal activity. Acute insults, e. g. status epilepticus, frequently cause the development of a chronic epileptic focus. The underlying pathomechanisms of this process, often referred to as "epileptogenesis", are still largely unknown. Both, in the context of epilepsy and migraine, accumulation of certain allelic variants has been reported. Several of those variants are localized in gene promoter regions. Due to the availability of human epileptic brain tissue derived from epilepsy-surgical removal of epileptogenic areas in pharmacoresistant patients, we were able to obtain information on the functional significance of these promoter variants within the framework of NGFNplus. Major results are as follows:

A.    Together with the projects Schoch, Beck, Nöthen and Cichon we have observed distinct mRNA signatures in hippocampal tissue after epilepsy surgery of patients with a priori drug resistance on Levetiracetam. Comprehensive expression analysis showed a significant increase of synapse-associated molecule transcripts. Some of those alterations are associated with an accumulation of specific variants of promoter alleles. These results suggest an "overexposure of targets"-mechanism as a potential explanation for a priori Levetiracetam drug resistance.

B.    We further demonstrated that in human epileptic brain tissue certain promoter variants are abundant in genes that are involved in the turn over of the major inhibitory neurotransmitter GABA. Corresponding transcriptional alterations can result in impairments of the homeostasis of GABA in the affected brain tissue of epilepsy patients. These data suggest potential new targets for improved pharmacotherapy.

C.    Serotonin-mediated signaling plays an important role in the pathogenesis of migraine. We have demonstrated in human brain tissue that transcription of a particular serotonin receptor (1A) is significantly altered by specific promoter allelic variants. In the context of these transcription alterations, promoter control by the transcription factor c-Jun has a prominent role. These data suggest a new type of ‘receptoropathy’ in human brain tissue.

D.    Together with colleagues from the NGFN network MooDS (Prof. Nöthen and Cichon) we have performed genome-wide complementary SNP-, expression- and promoter methylation studies. The corresponding analyses resulted in a functional mapping of complex gene regulation in human brain tissue.

In the future, our results for complex gene regulation in human brain tissue can contribute to significantly improved treatment strategies for episodic disorders of the central nervous system with inhibition of aberrant promoter activation mechanisms as new target structures. This progress was only possible due to the support by the NGFNplus.