Molecular Basis of Epilepsy
The group’s research aims at understanding the molecular basis of epilepsy syndromes through gene identification followed by functional studies, with the long-term aim of developing new therapies. The current focus is on progressive myoclonus epilepsies (PMEs).
The central focus of the group’s research is on disease mechanisms of EPM1, the most common PME disease, caused by biallelic partial loss-of-function mutations in the CSTB gene. CSTB-deficient (Cstb-/-) mice and patient-derived induced pluripotent stem cells (iPSC) are being utilized as models. CSTB was previously shown to have a role in regulation of neuronal survival during oxidative stress. Early microglial activation and neuroinflammation were shown to contribute to neuronal dysfunction and death in Cstb-/- mice. Recently, the group discovered that CSTB is also involved in the epigenetic regulation of mouse brain development defining through modulation of chromatin structure. The CSTB-deficency was shown to result in ectopic histone H3 cleavage and impaired mitochondrial respiration in neural stem cells, in line with complete loss of CSTB expression resulting in a brain disease with onset during embryonic development. To evaluate the biological processes contributing to EPM1 disease progression and to identify potential biomarkers in metabolic pathways, the group has performed multiomics analyses of transcriptomics, proteomics, lipidomics and metabolomics from postnatal Cstb-/- mouse brain, liver and serum, as well as of targeted metabolomics from patients’ serum. The data has revealed disturbances in lysosomal pathway contributing lipoprotein, lipid and cholesterol homeostasis, metabolic reprogramming with alterations in energy and mitochondrial oxidative metabolism, and oxidative stress resulting in neuroinflammation as important factors in EPM1. The data will be verified and utilized in the development novel treatments for EPM1 using EPM1-specific neurons and microglia from human pluripotent stem cells.
The group continues to dissect the molecular genetic basis of PMEs by exome sequencing in collaboration with Prof. Sam Berkovic’s group in Melbourne.
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Senior Scientists
Tarja Joensuu, PhD, Administrative Group Leader
Saara Tegelberg, PhD
Postdoctoral Researchers
Carina Lund, PhD
Doctoral Researchers
Julia Eriksson, MSc
Katarin Gorski, MSc
Staff
Paula Hakala, Laboratory Coordinator
Veronika Rezov, Laboratory Coordinator
In depth behavioral phenotyping unravels complex motor disturbances in Cstb-/- mouse, a model for progressive myoclonus epilepsy type 1.
Pollari E, Tegelberg S, Björklund H, Kälviäinen R, Lehesjoki AE, Haapalinna A. Frontiers in Behavioral Neuroscience. 2023.
Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice.
Gorski K, Jackson CB, Nyman TA, Rezov V, Battersby BJ, Lehesjoki AE. Frontiers in Molecular Neuroscience. 2023.
Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis.
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. Neurobiology of Disease. 2021.
Progressive myoclonus epilepsies – residual unsolved cases have marked genetic heterogeneity including genes in the dolichol-dependent protein glycosylation.
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. The American Journal of Human Genetics. 2021.
ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with impaired cerebellar granule cell migration.
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. Brain. 2017.
A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.
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. Nature Genetics. 2015.
Abnormal microglial activation in the Cstb-/- mouse, a model for progressive myoclonus epilepsy, EPM1.
Okuneva O, Körber I, Li Z, Tian L, Joensuu T, Kopra O, Lehesjoki A-E. Glia. 2015.
Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model for progressive myoclonus epilepsy, EPM1.
Tegelberg S, Kopra O, Joensuu T, Cooper JD, Lehesjoki A-E. Journal of Neuropathology & Experimental Neurology. 2012.
Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1.
Lehtinen MK, Tegelberg S, Schipper H, Su H, Zukor H, Manninen O, Kopra O, Joensuu T, Hakala P, Bonni A, Lehesjoki A-E. Journal of Neuroscience. 2009.
Mutations in the gene encoding cystatin B cause progressive myoclonus epilepsy (EPM1).
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. Science. 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
