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MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control.
Heiland, Mona; Connolly, Niamh M C; Mamad, Omar; Nguyen, Ngoc T; Kesavan, Jaideep C; Langa, Elena; Fanning, Kevin; Sanfeliu, Albert; Yan, Yan; Su, Junyi; Venø, Morten T; Costard, Lara S; Neubert, Valentin; Engel, Tobias; Hill, Thomas D M; Freiman, Thomas M; Mahesh, Arun; Tiwari, Vijay K; Rosenow, Felix; Bauer, Sebastian; Kjems, Jørgen; Morris, Gareth; Henshall, David C.
Afiliación
  • Heiland M; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Connolly NMC; FutureNeuro Science Foundation Ireland Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Mamad O; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Nguyen NT; FutureNeuro Science Foundation Ireland Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Kesavan JC; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Langa E; FutureNeuro Science Foundation Ireland Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Fanning K; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Sanfeliu A; FutureNeuro Science Foundation Ireland Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Yan Y; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Su J; FutureNeuro Science Foundation Ireland Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Venø MT; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Costard LS; FutureNeuro Science Foundation Ireland Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Neubert V; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Engel T; FutureNeuro Science Foundation Ireland Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Hill TDM; Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Freiman TM; FutureNeuro Science Foundation Ireland Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • Mahesh A; Interdisciplinary Nanoscience Centre, Aarhus University, 8000 Aarhus C, Denmark.
  • Tiwari VK; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
  • Rosenow F; Omiics, 8200 Aarhus N, Denmark.
  • Bauer S; Interdisciplinary Nanoscience Centre, Aarhus University, 8000 Aarhus C, Denmark.
  • Kjems J; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
  • Morris G; Interdisciplinary Nanoscience Centre, Aarhus University, 8000 Aarhus C, Denmark.
  • Henshall DC; Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
Proc Natl Acad Sci U S A ; 120(30): e2216658120, 2023 07 25.
Article en En | MEDLINE | ID: mdl-37463203
There remains an urgent need for new therapies for treatment-resistant epilepsy. Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bidirectional control of sodium channel expression are needed. MicroRNAs (miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the antiseizure medicine cannabidiol, and plasma from patients with treatment-resistant epilepsy, converge on a single target-miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a, Scn2a, and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking miR-335-5p also increased voltage-gated sodium currents and SCN1A, SCN2A, and SCN3A expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect neuronal excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: MicroARNs / Epilepsia / Células Madre Pluripotentes Inducidas / Canales de Sodio Activados por Voltaje Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: MicroARNs / Epilepsia / Células Madre Pluripotentes Inducidas / Canales de Sodio Activados por Voltaje Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Estados Unidos