Group Lehesjoki

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

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 Wariovaara, University of Helsinki

Contact

    • Anna-Elina Lehesjoki

      MD, PhD, Professor, Group Leader

    • Tel:
      +358 50 5058894

    • Contact
    • Tarja Joensuu

      PhD, Administrative Group Leader

    • Tel:
      +358 2941 2580

    • Contact