AG Lerche

"Mechanismen genetischer Epilepsien"

Our group is interested to link the molecular mechanisms of defined, mainly genetic, neurological diseases with their clinical symptoms. The main goals are (i) to find out specific disease-causing genetic defects, (ii) understand their molecular and cellular pathomechanisms to ultimately (iii) improve existing or develop new therapies. The research is concentrated on diseases with disturbed neuronal excitability caused by mutations in ion channels, receptors or transporters. These have the advantage that we can examine their gating mechanisms in molecular detail using electrophysiological techniques such as patch clamping.

The current main research focus comprises the genetics, pathophysiology and therapeutic perspectives of idiopathic epilepsies. Epilepsy affects approximately 3% of people during their lifetime. An estimated 40% of all epilepsy patients suffer from so-called “idiopathic epilepsies”, which are genetic in origin and not caused by structural or metabolic brain abnormalities. Almost all of the mutations identified so far to be associated with idiopathic epilepsy syndromes affect genes encoding ion channels. Numerous ion channels tune the neuronal transmembrane voltage, by opening and closing (“gating”) in response to either synaptic neuromediators (ligand-gated channels) or changes in the voltage itself (voltage-gated channels). In this way genetic mutations affecting these channels can alter neuronal excitability and potentially drive a network of neurons into synchrony to promote a seizure. This conclusion is further supported by the fact that most of the antiepileptic drugs in clinical use today modulate different types of ion channels.

Our group has a long-standing experience with structure-function analysis and the gating properties of ion channels using molecular biological and electrophysiological techniques. We have been functionally characterizing disease-causing mutations of different ion channels including voltage-gated sodium, potassium, calcium and chloride channels as well as ligand-gated channels (GABA receptors, see picture). Most of our previous and a lot of ongoing studies have been carried out in heterologous expression systems, i.e. channels are expressed in a cell line that usually does contain this molecule but provides the possibility to study its molecular function. We are now exploring the functional implications of disease-related mutations in neurons and determining the specific roles of affected channels in the brain. We use neuronal cultures and genetically altered animals to assess the cellular and subcellular localization of ion channels, targeting mechanisms and functional analyses of wild type and mutant channels in single neurons and brain slices using immunohistochemistry, imaging of fluorescent fusion proteins and electrophysiology.

Exploring novel pharmacotherapies and molecular pharmacological mechanisms of antiepileptic drugs acting on ion channels is another field of our interest. In collaboration with other groups, we have started to characterize the function of ion channels and synaptic transmission in stem cells.

 

Group leader:

Holger Lerche, MD

 

Postdocs:

Snezana Maljevic, PhD

Georgeta Teodorescu, PhD

Yvonne Weber, MD

Thomas Wuttke, MD

 

PhD students:

Yunxiang Liao, M. Sc., MD (China)

Simone Schubert, Dipl. Biol.

 

MD students:

Felicitas Becker, cand. med.

Anne-Gret Heidrich, cand. med.

Miriam Jacob, cand. med.

Judith Kempfle, cand med.

Jeannette Liebrich, cand. med.

Georgios Naros, cand. med.

 

Technicians:

Astrid Bellan-Koch

Alberto Vargas

 

Former group members:

Wasima Akbari, technician

Alexi Alekov, PhD

Sigrid Bail, technician

Dragica Blazevic, technician

Ernst-Jürgen Derra, cand. med.

Günay Dönmez, cand. med.

Jacqueline Fernandez, PhD

Julia Geiger, MD

Stefanie Hoffmann, MD

Skevos Karafyllakis, cand. med.

Nancy Meyer, technician

Wolfgang Peter, MD, Dipl. Phys.

Oana Popa, PhD

Masmusdur Rahman, PhD

Achim Riecker, technician

Steffen Schumacher, cand. med.

 

• DFG: Heisenberg fellowship
• DFG: Differential role of the voltage-gated sodium channels Nav1.1 and Nav1.2
• EU: ‘Epicure’, Integrated project on functional genomics and neurobiology of epilepsy (link: www.epicureproject.eu/home.aspx)
• BMBF: Nationales Genomforschungsnetz (NGFN2), subnet epilepsy
• Land Baden-Württemberg: Landesforschungsschwerpunkt‚ 'Molecular determinants of compartimentalization of neuronal cells'
• Universität Ulm

Original papers:

Genetics, pathophysiology and therapy of idiopathic epilepsies

• Lerche H, Biervert C, Alekov AK, Schleithoff L, Lindner M, Klingler W, Bretschneider F, Mitrovic N, Jurkat-Rott K, Bode H, Lehmann-Horn F, Steinlein OK. A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol 1999;46:305-12.
• Alekov AK, Rahman MM, Mitrovic N, Lehmann-Horn F, Lerche H. A sodium channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro. J Physiol 2000;529:533-9.
• Alekov AK, Rahman MM, Mitrovic N, Lehmann-Horn F, Lerche H. Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man. Eur J Neurosci 2001;13:2171-6.
• Lerche H, Weber YG, Baier H, Jurkat-Rott K, Kraus de Camargo O, Ludolph AC, Bode H, Lehmann-Horn F. Generalized epilepsy with febrile seizures plus: Further heterogeneity in a large family. Neurology 2001;57:1191-8.
• Haug K*, Warnstedt M*, Alekov AK*, Sander T, Ramirez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger JS, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Muller-Newen G, Propping P, Elger CE, Fahlke C*, Lerche H*§, Heils A*§. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet 2003;33:527-32. *contributed equally, §corresponding authors
• Maljevic S, Lerche C, Seebohm G, Alekov AK, Busch AE, Lerche H. C-terminal interaction of KCNQ2 and KCNQ3 K+ channels. J Physiol 2003;548:353-60.
• Weber YG, Berger A, Hallbach A, Bebek N, Maier S, Karafyllakes S, Fukuyama Y, Hickel C, Kurlemann G, Neubauer B, Osawa M, Püst B, Rating D, Saito K, Stephani U, Lehmann-Horn F, Jurkat-Rott K, Lerche H. Benign familial infantile convulsions: Linkage to chromosome 16p12-q12 in 14 families. Epilepsia 2004;45:601-9.
• Krampfl K*, Maljevic S, Cossette P, Ziegler E, Rouleau GA, Lerche H*, Bufler J. Molecular analysis of the A322D mutation in the a1-subunit of the GABAA receptor causing juvenile myoclonic epilepsy. Eur J Neurosci 2005;22:10-20. *corresponding authors
• Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H. The new anticonvulsant Retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharm 2005;67:1009-17.
• Weber YG, Geiger J, Kaempchen K, Lindenberg K, Landwehrmeyer B, Sommer C, Lerche H. Immunohistochemical analysis of KCNQ2 potassium channels in adult and developing mouse brain. Brain Res 2006;1077:1-6.
• Maljevic S, Krampfl K, Cobilanschi J, Tilgen N, Beyer S, Weber YG, Schlesinger F, Ursu D, Melzer W, Cossette P, Bufler J, Lerche H*, Heils A*. A mutation in the the GABAA receptor a1-subunit is associated with absence epilepsy. Ann Neurol 2006;59:983-7. *corresponding authors
• Hunter*, Maljevic M*, Shankar A, Siegel A, Olson L, Weissman B, Holt P, Lerche H§, Escayg A§. Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy. Neurobiol Dis 2006;24:194-201. *contributed equally, §corresponding authors
• Hempelmann A, Taylor KP, Heils A, Lorenz S, Prud’Homme JF, Nabbout R, Dulac O, Rudolf G, Zara F, Bianchi A, Robinson R, Gardiner RM, Covanis A, Lindhout D, Stephani U, Elger CE, Weber YG, Lerche H, Nürnberg P, Kron KL, Scheffer IE, Mulley JC, Berkovic SF, Sander T. Exploration of the Genetic Architecture of Idiopathic Generalized Epilepsies. Epilepsia 2006;47:1682-90

 

Other ion channel disorders

• Wuttke T, Jurkat-Rott K, Paulus W, Garncarek M, Lehmann-Horn F, Lerche H. Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology, in press

 

Sodium channelopathies of skeletal muscle and molecular mechanism of sodium channel inactivation

• Lerche H, Heine R, Pika U, George AL Jr, Mitrovic N, Browatzki M, Weiss T, Rivet-Bastide M, Franke C, Lomonaco M, Ricker K, Lehmann-Horn F. Human sodium channel myotonia: Slowed channel inactivation due to substitutions for a glycine within the III-IV linker. J Physiol 1993;470,13-22.
• Mitrovic N, George AL, Lerche H, Wagner S, Fahlke Ch, Lehmann-Horn F. Different effects on gating of three myotonia causing mutations in the inactivation gate of the human muscle sodium channel. J Physiol 1995;487:107-14.
• Lerche H, Mitrovic N, Dubowitz V, Lehmann-Horn F. Paramyotonia congenita: The R1448P sodium channel mutation in adult human skeletal muscle. Ann Neurol 1996;39:599-608.
• Lerche H, Peter W, Fleischhauer R, Pika-Hartlaub U, Malina T, Mitrovic N, Lehmann-Horn F. Role in fast inactivation of the IV/S4-S5 loop of the human muscle Na+ channel probed by cysteine mutagenesis. J Physiol 1997;505:345-52.
• Mitrovic N, George AL, Rüdel R, Lehmann-Horn F, Lerche H. Mutant channels contribute < 50% to Na+ current in paramyotonia congenita muscle. Brain 1999;122:1085-92.
• Peter W, Mitrovic N, Schiebe W, Lehmann-Horn F, Lerche H. A human muscle sodium channel mutation in the voltage sensor IV/S4 affects channel block by the pentapeptide KIFMK. J Physiol 1999;518:13-22.
• Jurkat-Rott K, Mitrovic N, Hang C, Kouzmenkine A, Iaizzo P, Herzog J, Lerche H, Nicole S, Vale-Santos J, Chauveau D, Fontaine B, Lehmann-Horn F. Voltage sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci USA 2000;97:9549-54.
• Popa MO, Alekov AK, Bail S, Lehmann-Horn F, Lerche H. Cooperative effect of S4-S5 loops in domains D3 and D4 on fast inactivation of the sodium channel. J Physiol 2004;561:39-51.
• The YK, Fernandez J, Popa MO, Timmer J, Lerche H. Modeling of single non-inactivating Na+ channels: evidence for two open and several fast inactivated states. Biophys J 2006;90:3511-3522.

 

Stem cells (collaboration with A. Storch, Dresden)

• Hermann A, Gastl R, Liebau S, Popa O, Fiedler J, Boehm BO, Lerche H, Schwarz J, Brenner R, Storch A. Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 2004;117:4411-22.
• Hermann A, Maisel M, Liebau S, Gerlach M, Kleger A, Schwarz J, Kim KS, Antoniadis G, Lerche H, Storch A. Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells. J Neurochem 2006;98:629-40.
• Maisel M, Herr A, Milosevic J, Hermann A, Habisch HJ, Schwarz S, Kirsch M, Antoniadis G, Brenner R, Hallmeyer-Elgner S, Lerche H, Schwarz J, Storch A..Transcription profiling of adult and fetal human neuroprogenitors identifies divergent paths to maintain the neuroprogenitor cell state. Stem cells 2007;25:1231-40.

 

Invited reviews:

• Lerche H, Mitrovic N, Jurkat-Rott K, Lehmann-Horn F. Ionenkanalerkrankungen - Allgemeine Charakteristika und Pathomechanismen. Dt Ärztebl 2000;97:A-1826-31 (Heft 26).
• Lerche H, Mitrovic N, Jurkat-Rott K, Lehmann-Horn F. Ionenkanalerkrankungen: Krankheitsbilder. Dt Ärztebl 2000;97:A-1902-7 (Heft 27).
• Lerche H, Jurkat-Rott K, Lehmann-Horn F. Ion channels and epilepsy. Am J Med Gen (Sem Med Gen) 2001;106:146-59.
• Jurkat-Rott K, Lerche H, Lehmann-Horn F. Skeletal muscle channelopathies. J Neurol 2002;249:1493-502.
• Lerche H, Weber YG, Heils A. Genetik und Pathophysiologie idiopathischer Epilepsien. Nervenheilkunde 2004;23:188-96.
• Lerche H, Weber YG, Jurkat-Rott K, Lehmann-Horn F. Ion channel defects in idiopathic epilepsies. Curr Pharm Des 2005;11:2737-52.
• Maljevic S, Lerche H. Ion channel dysfunctions in idiopathic epilepsies. Curr Med Lit Neurol 2006;22:33-47.
• Wuttke T, Lerche H. Novel anticonvulsant drugs targeting voltage-dependent ion channels. Exp Opin Invest Drugs 2006;15:1167-77.

 

Book chapters:

• Mitrovic N, Lerche H. Sodium and calcium channelopathies of sarcolemma: periodic paralyses, paramyotonia congenita and potassium-aggravated myotonia. In: Channelopathies – Common Mechanisms in Aura, Arrhythmia and Alkalosis. Ed.: Lehmann-Horn F, Jurkat-Rott K. Elsevier-Science, 2000, pp 3-32.
• Heils A, Lerche H. Epilepsien. In: Neurogenetik, 2. Auflage. Ed.: Riess O, Schöls L. Kohlhammer Verlag, 2002, pp 253-71.
• Jurkat-Rott K, Lerche H, Lehmann-Horn F. Migräne. In: Neurogenetik, 2. Auflage. Ed.: Riess O, Schöls L. Kohlhammer Verlag, 2002, pp 290-7.
• Jurkat-Rott K, Lerche H, Lehmann-Horn F. Episodische Ataxien. In: Neurogenetik, 2. Auflage. Ed.: Riess O, Schöls L. Kohlhammer Verlag, 2002, pp 409-14.
• Lerche H, Mitrovic N, Jurkat-Rott K, Lehmann-Horn F. Nichtdystrophische Myotonien und periodische Paralysen. In: Neurogenetik, 2. Auflage. Ed.: Riess O, Schöls L. Kohlhammer Verlag, 2002, pp 515-23.
• Lehmann-Horn, Lerche H, Jurkat-Rott K. Skeletal muscle channelopathies: myotonias, periodic paralyses and malignant hyperthermia. In: Stålberg E (Ed). Clinical neurophysiology of disorders of muscle and neuromuscular junction, including fatigue. Handbook of Clinical Neurophysiology, Elsevier, 2003, Vol. 2, Chapter 23, pp 457-83.
• Lerche H, Lehmann-Horn F. Compounds acting on ion channels. In: Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics. Ed.: Beal F, Lang A, Ludolph AC. Cambridge University Press, 2005, pp141-5.
• Lerche H, Maljevic S, Weber YG. Genetics and pathophysiological mechanisms in idiopathic epilepsies. In: Plecko B (Ed). Symposia Proceedings: Metabolic and genetic infantile epilepsies, Int. Symposium ‘Focus on Neuropediatrics’ 2005 (Fulda), SPS Publications, Heilbronn, 2006, pp 58-89.
• 'Encyclopedia of Molecular Mechanisms of Disease', Lehmann-Horn F and Lerche H, Co-Editors for the Neurosciences, Editor in Chief: Lang F, Springer Verlag, in preparation.

Applied Physiology - Univesity of Ulm

 

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