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Aberrant expression of miR-218 and miR-204 in human mesial temporal lobe epilepsy and hippocampal sclerosis-Convergence on axonal guidance

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Sanne Simone Kaalund, Department of Cellular and Molecular Medicine, Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Danmark
  • Morten T Venø, Danmark
  • Mads Bak, Department of Cellular and Molecular Medicine, Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Danmark
  • Rikke S Møller, Department of Cellular and Molecular Medicine, Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Danmark
  • Henning Laursen, Laboratory of Neuropathology, Copenhagen University Hospital , Danmark
  • Flemming Madsen, Department of Neurosurgery, Copenhagen University Hospital, Danmark
  • Helle Broholm, Laboratory of Neuropathology, Copenhagen University Hospital , Danmark
  • Bjørn Quistorff, Laboratory of Neuropathology, Copenhagen University Hospital , Danmark
  • Peter Uldall, Department of Pediatrics, Copenhagen University Hospital Rigshospitalet, Denmark., Danmark
  • Niels Tommerup, Department of Cellular and Molecular Medicine, Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Danmark
  • Sakari Kauppinen, Department of Haematology, Aalborg University Hospital, Aalborg, Denmark., Danmark
  • Anne Sabers, Department of Neurology, The Epilepsy Clinic, Copenhagen University Hospital, Danmark
  • Kees Fluiter, Department of Neurogenetics, Academic Medical Center, University of Amsterdam, Holland
  • Lisbeth Birk Møller, Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Danmark
  • Anne Yaël Nossent, Laboratory for Molecular Cardiology, Department of Biomedical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Danmark
  • Asli Silahtaroglu, Department of Cellular and Molecular Medicine, Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Danmark
  • Jørgen Kjems
  • Eleonora Aronica, SEIN–Stichting Epilepsie Instellingen Nederland, Holland
  • Zeynep Tümer, Department of Cellular and Molecular Medicine, Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Danmark
OBJECTIVE:
Mesial temporal lobe epilepsy (MTLE) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis (HS), which is characterized by pronounced loss of hippocampal pyramidal neurons. microRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE and HS.

METHODS:
miRNA expression was quantified in hippocampal specimens from human patients using miRNA microarray and quantitative real-time polymerase chain reaction RT-PCR, and by RNA-seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of miRNAs in the human hippocampus. The potential effect of miRNAs on targets genes was investigated using the dual luciferase reporter gene assay.

RESULTS:
miRNA expression profiling showed that 25 miRNAs were up-regulated and 5 were down-regulated in hippocampus biopsies of MTLE/HS patients compared to controls. We showed that miR-204 and miR-218 were significantly down-regulated in MTLE and HS, and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR-204 and miR-218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO1, GRM1, SLC1A2, and GNAI2, as bona fide targets of miR-218. GRM1 was also shown to be a direct target of miR-204.

SIGNIFICANCE:
miR-204 and miR-218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS.
OriginalsprogEngelsk
TidsskriftEpilepsia
Vol/bind55
Nummer12
Sider (fra-til)2017-2027
Antal sider11
ISSN0013-9580
DOI
StatusUdgivet - dec. 2014

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