Molecular Basis of Epilepsy
Our 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 with the long-term aim of developing new therapies.
A central focus of our research is on disease mechanisms of progressive myoclonus epilepsy EPM1 utilizing cystatin B -deficient (Cstb-/-) mice and patient-derived induced pluripotent stem cells (iPSC) as models. We previously showed that cystatin B has a role in regulating neuronal survival during oxidative stress and that early microglial activation and neuroinflammation centrally contribute to neuronal dysfunction and death in Cstb-/- mice. More recently, we demonstrated a role for cystatin B as a regulator of chromatin structure through modulation of histone H3 clevage during neurogenesis. Our research currently focuses on investigating the molecular mechanisms associated with epigenetic, synaptic and microglial dysfunction in EPM1 models. Within the Business Finland -supported “New Modalities Ecosystem” -project, coordinated by Orion, the group participates in the discovery of metabolic pathways contributing to progression of rare neurodegenerative diseases.
Gene identification is focused on progressive myoclonus epilepsy syndromes and severe early childhood-onset progressive encephalopathies using exome and genome sequencing. The group recently identified KCNC1 as an important novel underlying cause of progressive myoclonus epilepsies we have shown that the residual unsolved cases have highly heterogeneous genetic etiologies, including genes of the dolichol-dependent protein glycosylation pathway. 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 Researchers
Carina Lund, PhD
Doctoral Researchers
Julia Eriksson, MSc
Katarin Gorski, MSc
Staff
Paula Hakala, Laboratory Coordinator
Veronika Rezov, Laboratory Coordinator
Pollari E, Tegelberg S, Björklund H, Kälviäinen R, Lehesjoki AE, Haapalinna A.
In depth behavioral phenotyping unravels complex motor disturbances in Cstb-/- mouse, a model for progressive myoclonus epilepsy type 1.
Front Behav Neurosci 21:17:1325051, 2023. doi: 10.3389/fnbeh.2023.1325051.
Gorski K, Jackson CB, Nyman TA, Rezov V, Battersby BJ, Lehesjoki AE.
Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice.
Front Mol Neurosci 12:16:1175851, 2023. doi: 10.3389/fnmol.2023.1175851.
Daura E, Tegelberg S, Yoshihara M, Jackson C, Simonetti F, Aksentjeff K, Ezer S, Hakala P, Katayama S, Kere J, Lehesjoki A-E, Joensuu T.
Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis.
Neurobiol Dis 156:105418, 2021 (doi: 10.1016/j.nbd.2021.105418)
Courage C, Oliver KL, Park EJ, Cameron JM, Grabińska KA, Muona M, Canafoglia L, Gambardella A,Said E, Afawi Z, Baykan B, Brandt C, di Bonaventura C, Chew HB, Criscuolo C, Dibbens LM, Castellotti B, Riguzzi P, Labate A,Filla A,Giallonardo AT, Jackson CB, Joensuu T, Damiano JA, Kivity S, Korczyn A, Palotie A, Striano P, Uccellini D, Giuliano L, Andermann E, Scheffer IE, Michelucci R, Bahlo M, Franceschetti S, Sessa WC, Berkovic SF, Lehesjoki A-E.
Progressive myoclonus epilepsies – residual unsolved cases have marked genetic heterogeneity including genes in the dolichol-dependent protein glycosylation.
Am J Hum Genet 108:722-738, 2021 (doi: 10.1016/j.ajhg.2021.03.013)
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]
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
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
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
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
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
Prof. Sam Berkovic, University of Melbourne, Australia / co-coordinator of the PME genetics consortium
Prof. Amanda Sierra, University of the Basque Country, Leioa, Spain
Prof. Reetta Kälviäinen, University of Eastern Finland
Dr. Brendan Battersby, University of Helsinki
Dr. Christopher Jackson, University of Helsinki
Prof. Anu Wartiovaara, University of Helsinki
Docent Päivi Saavalainen, Folkhälsan Research Center and University of Helsinki
Prof. Berge Minassian, The University of Texas Southwestern Medical Center, USA
Folkhälsan Research Foundation
Sigrid Jusélius Foundation
Medicinska understödsföreningen Liv och Hälsa (“Life and Health Medical Fund”)
The Medical Society of Finland (Finska Läkaresällskapet)
Business Finland
