Group Lehesjoki
Molecular Basis of EpilepsyOur research aims at understanding the molecular basis of epilepsy syndromes through identification of the underlying defective genes, followed by functional analyses of the gene products and characterization of disease mechanisms in cellular and animal models.
A central focus of research is on disease mechanisms of progressive myoclonus epilepsy EPM1 utilizing cystatin B –deficient (Cstb-/-) mice as a model. We previously showed that cystatin B has a role in regulating neuronal survival during oxidative stress, which is at least partly mediated by cathepsin B signaling. More recently, we demonstrated that early microglial activation and neuroinflammation centrally contribute to neuronal dysfunction and death in Cstb-/- mice. We are currently investigating the molecular mechanisms associated with microglial activation and dysfunction, a long-term aim being the identification of novel target molecules and the development of anti-inflammatory therapies.
Gene identification is focused on progressive myoclonus epilepsy (PME) syndromes and severe early childhood-onset progressive encephalopathies using exome sequencing. The group recently reported identification of a recurrent de novo mutation in KCNC1 causing a dominant-negative loss-of-function effect on the KV3 voltage-gated potassium channel as a major underlying cause of PME worldwide. The group is also involved in analysis of the molecular genetics basis of generalized genetic epilepsies, which are multifactorial in origin. Gene identification involves collaboration with large international consortia. The consortium aiming at deciphering the molecular genetic spectrum of PMEs is headed by the PI and Prof. Sam Berkovic in Melbourne.
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Senior Scientists
Tarja Joensuu, PhD, Administrative Group Leader
Saara Tegelberg, PhD
Clinical Scientists
Anna-Kaisa Anttonen, MD, PhD
Tarja Linnankivi, MD, PhD
Post-Doctoral Scientists
Carolina Courage, MD
Graduate Students
Eduard Daura Sarroca, MSc
Katarin Gorski, MSc
Undergraduate Students
Katri Aksentjeff, BSc
Staff
Paula Hakala, Laboratory Coordinator
Veronika Rezov, Laboratory Coordinator
Katja Pylsy, Research Assistant
Pennacchio LA, Lehesjoki A-E, Stone NE, Willour VL, Virtaneva K, Miao J, D'Amato E, Ramirez L, Faham M, Koskiniemi M, Warrington J, Norio R, de la Chapelle A, Cox DR, Myers RM. Mutations in the gene encoding cystatin B cause progressive myoclonus epilepsy (EPM1). Science 271: 1731-1734, 1996
Ranta S, Zhang Y, Ross B, Lonka L, Takkunen E, Messer A, Sharp J, Wheeler R, More S, Liu W, Soares MB, de Fatima Bonaldo M, Hirvasniemi A, de la Chapelle A, Gilliam TC, Lehesjoki A-E. The neuronal ceroid lipofuscinosis in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nature Genet 23: 233-236, 1999
Kolehmainen J, Black GCM, Saarinen A, Chandler K, Träskelin A-L, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns J-P, de la Chapelle A, Lehesjoki A-E. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet 72: 1359-1369, 2003
Lehtinen MK, Tegelberg S, Schipper H, Su H, Zukor H, Manninen O, Kopra O, Joensuu T, Hakala P, Bonni A, Lehesjoki A-E. Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J Neurosci 29:5910-5915, 2009
Polvi A, Linnankivi T, Kivelä T, Herva R, Keating JP, Mäkitie O, Pareyson D, Vainionpää L, Lahtinen J, Hovatta I, Pihko H, Lehesjoki A-E. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet 90: 540-549, 2012
Tegelberg S, Kopra O, Joensuu T, Cooper JD, Lehesjoki A-E. Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model for progressive myoclonus epilepsy, EPM1. J Neuropathol Exp Neurol 71: 40-53, 2012
Okuneva O, Körber I, Li Z, Tian L, Joensuu T, Kopra O, Lehesjoki A-E. Abnormal microglial activation in the Cstb-/- mouse, a model for progressive myoclonus epilepsy, EPM1. Glia 63: 400-411, 2015
Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, Joensuu T, Canafoglia L, Franceschetti S, Michelucci R, Markkinen S, Heron SE, Hildebrand M, Andermann E, Andermann F, Antonio Gambardella A, Tinuper P, Licchetta L, Scheffer IE, Criscuolo C, Filla A, Ferlazzo E, Ahmad J, Ahmad A, Baykan B, Said E, Topcu M, Riguzzi P, King MD, Ozkara C, Andrade DA, Engelsen BA, Crespel A, Lindenau M, Lohmann E, Saletti V, Massano J, Privitera M, Espay AJ, Kauffmann B, Duchowny M, Møller RS, Straussberg R, Afawi Z, Ben-Zeev B, Samocha KE, Daly MJ, Petrou S, Lerche H, Palotie A, Lehesjoki A-E. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nature Genet 47: 39-46, 2015
Muona M, Ishimura R, Laari A, Ichimura Y, Linnankivi T, Keski-Filppula R, Herva R, Rantala H, Paetau A, Pöyhönen M, Obata M, Uemura T, Karhu T, Bizen N, Takebayashi H, Anttonen A-K,14, Tanaka K, Palotie A, Waguri S, Lehesjoki A-E, Komatsu M. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier to severe infantile-onset encephalopathy. Am J Hum Genet 99: 683-694, 2016
Anttonen A-K, Laari A, Kousi M, Yang YJ, Jääskeläinen T, Somer M, Siintola E, Jakkula E, Muona M, Tegelberg S, Lönnqvist T, Pihko H, Valanne L, Paetau A, Hästbacka J, Kopra O, Joensuu T, Katsanis N, Lehtinen MK, Palvimo JJ, Lehesjoki A-E. ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with impaired cerebellar granule cell migration. Brain 2017 Mar 1. doi: 10.1093/brain/awx040. [Epub ahead of print]
Folkhälsan Research Foundation
University of Helsinki
Sigrid Jusélius Foundation
Medicinska understödsföreningen Liv och Hälsa (“Life and Health Medical Fund”)
Business Finland
Prof. Sam Berkovic, University of Melbourne, Australia / co-coordinator of the PME genetics consortium
EuroEpinomics CoGIE and RES consortia, Epi25 consortium
Prof. Annamaria Vezzani, Mario Negri Institute for Pharmacological Research, Milan, Italy
Prof. Amanda Sierra, University of the Basque Country, Leioa, Spain
Prof. Esa Korpi, University of Helsinki
Prof. Kari Eklund, University of Helsinki
Prof. Reetta Kälviäinen, University of Eastern Finland
Doc. Maija Wessman, Folkhälsan Research Center
Prof. Juha Kere, Folkhälsan Research Center and Karolinska Institute
