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 Scientists
Carina Lund, PhD
Graduate Students
Eduard Daura Sarroca, MSc
Katarin Gorski, MSc
Staff
Paula Hakala, Laboratory Coordinator
Veronika Rezov, Laboratory Coordinator
Students
Marina Díaz Wallach, Erasmus Student
Canafoglia L, Franceschetti S, Gambardella A, Striano P, Giallonardo AT, Tinuper P, Di Bonaventura C, Michelucci R, Ferlazzo E, Granata T, Magaudda A, Licchetta L, Filla A, La Neve A, Riguzzi P, Cantisani TA, Fanella M, Castellotti B, Gellera C, Bahlo M, Zara F, Courage C, Lehesjoki A-E, Oliver KL, Berkovic SF. Progressive myoclonus epilepsies: diagnostic yield with next generation sequencing in previously unsolved cases. Neurol Genet. 2021 Nov 12;7(6):e641. doi: 10.1212/NXG.0000000000000641. https://pubmed.ncbi.nlm.nih.gov/34786481/
Bott LC, Forouhan M, Lieto M, Sala AJ, Ellerington R, Johnson JO, Speciale AA, Criscuolo C, Filla A, Chitayat D, Alkhunaizi E, Shannon P, Nemeth AH; Italian Undiagnosed Diseases Network, Angelucci F, Lim WF, Striano P, Zara F, Helbig I, Muona M, Courage C, Lehesjoki A-E, Berkovic SF; ATPase Consoortium, Fischbeck KH, Brancati F, Morimoto RI, Wood MJA, Rinaldi C. Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy. Brain Commun. 2021 Oct 18;3(4):fcab245. doi: 10.1093/braincomms/fcab245. https://pubmed.ncbi.nlm.nih.gov/34909687/
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, LehesjokiA-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)
Mazzola L, Oliver KL, Labalme A, Baykan B, Muona M, Joensuu TH, Courage C, Charton N, Borsani G, Alix E, Ramond F, Touraine R, Bahlo M, Bebek N, Berkovic SF, Lehesjoki A-E, Lesca G. Progressive myoclonus epilepsy caused by a homozygous splicing variant of SLC7A6OS. Ann Neurol 89:402-407, 2021 (doi: 10.1002/ana.25941)
Gorski K, Spoljaric A, Nyman T, Kaila K, Battersby BJ, Lehesjoki A-E. Quantitative changes in the mitochondrial proteome of cerebellar synaptosomes from preclinical cystatin B-deficient mice. Front Mol Neurosci 13:1-13, 2020 (doi: 10.3389/fnmol.2020.570640)
Sierra-Torre V, Plaza-Zabala A, Bonifazi P, Abiega O, Díaz-Aparicio I, Tegelberg S, Lehesjoki A-E, Valero J, Sierra A. Microglial phagocytosis dysfunction is related to local neuronal activity in a genetic model of epilepsy. Epilepsia 61:2593-2608, 2020 (doi: 10.1111/epi.16692)
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, Fukata Y, Anttonen A-K, Laari A, Palotie A, Pihko H, Lönnqvist T, Valanne L, Somer M, Fukata M, Lehesjoki A-E. Dysfunctional ADAM22implicated in progressive encephalopathy with cortical atrophy and epilepsy. Neurol Genet 2: e46, 2016 (doi: 10.1212/NXG.0000000000000046)
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
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
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
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
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
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
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
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
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
Prof. Juha Kere, Folkhälsan Research Center and Karolinska Institutet
Dr. Shintaro Katayama, Folkhälsan Research Center and Karolinska Institutet
Dr. Brendan Battersby, University of Helsinki
Dr. Christopher Jackson, University of Helsinki
Prof. Anu Wartiovaara, University of Helsinki
