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Epigenetische Pathomechanismen der Epileptogenese

Epigenetic pathomechanisms in epileptogenesis

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Zusammenfassung

Viele Läsionen im Gehirn können zu einer Epilepsie führen. Allerdings sind weder Anfallsbeginn noch Krankheitsverlauf oder das Ansprechen der antikonvulsiven Therapie individuell vorhersehbar. Auch die Pathomechanismen der Epileptogenese sind bislang wenig bekannt. Die verfügbaren und neu entwickelten Antiepileptika zielen meistens auf die Hemmung der Membranerregbarkeit oder der synaptischen Übertragung, ohne dass sich wirklich neue Möglichkeiten für die Behandlung pharmakoresistenter Epilepsien eröffnet haben. Ganz neue Impulse in dieser Hinsicht erhofft man sich durch die „epigenetische Medizin“. „Epigenetik“ wird als diejenige Veränderung der Erbsubstanz definiert, die Information unabhängig von der DNA-Sequenz engrammiert, z. B. durch DNA- oder Histonmethylierung. Epigenetische Mechanismen stellen somit fundamentale Regulationsprozesse für die zeitliche und räumliche Expression spezifischer Gene im Zentralnervensystem dar und spielen bei der Gehirnentwicklung und Alterung, aber auch bei synaptischer Plastizität sowie Gedächtnisbildung eine wichtige Rolle. Darüber hinaus wurden aberrante epigenetische Modifikationen bei zahlreichen neurologischen Erkrankungen beobachtet, wie z. B. Schizophrenie oder spinale Muskelatrophie. Die Autoren postulieren, dass epigenetische Pathomechanismen auch der Entstehung und Progression epileptischer Anfälle zugrunde liegen. Die systematische wissenschaftliche Untersuchung epigenetischer Pathomechanismen kann zudem neue Strategien für die Entwicklung pharmakologisch relevanter Zielmoleküle hervorbringen, und dieser Ansatz wird durch das neue europäische Verbundprojekt EpiGENet im Rahmen des Programms EuroEPINOMICS gefördert.

Abstract

Recent studies point to a pathogenic role of epigenetic chromatin modifications during epileptogenesis. Epigenetic mechanisms are covalent posttranslational modifications of histone proteins and DNA, which can produce lasting alterations in chromatin structure and gene expression. They are increasingly recognized as fundamental regulatory processes in central nervous system development, synaptic plasticity, and memory, and also play a role in neurological disorders, such as schizophrenia or spinal muscular atrophy. The authors propose that the “methylation hypothesis” addresses the intriguing issue of seizure-induced epigenetic chromatin modifications, which aggravate the epileptogenic condition by targeting candidate epileptogenesis gene expression. Unravelling epigenetic pathomechanisms will open also new strategies to identify molecular targets for pharmacological treatment in epilepsies. This project will be supported by EpiGENet, one of four consortia from the newly established European EuroEPINOMICS initiative.

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Authors and Affiliations

  1. Neuropathologisches Institut, Universitätsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Deutschland

    I. Blümcke & K. Kobow

  2. Neuropathologisches Institut, Universitätsklinikum Bonn, Bonn, Deutschland

    A.J. Becker

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  1. I. Blümcke
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  2. K. Kobow
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  3. A.J. Becker
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Correspondence to I. Blümcke.

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Blümcke, I., Kobow, K. & Becker, A. Epigenetische Pathomechanismen der Epileptogenese. Z. Epileptol. 24, 118–122 (2011). https://doi.org/10.1007/s10309-011-0171-0

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  • DOI: https://doi.org/10.1007/s10309-011-0171-0

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