Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Irit Reichenstein, Chen Eitan, Sandra Diaz-Garcia, Guy Haim, Iddo Magen, Aviad Siany, Mariah L Hoye, Natali Rivkin, Tsviya Olender, Beata Toth, Revital Ravid, Amitai D Mandelbaum, Eran Yanowski, Jing Liang, Jeffrey K Rymer, Rivka Levy, Gilad Beck, Elena Ainbinder, Sali M K Farhan, Kimberly A LennoxNicole M Bode, Mark A Behlke, Thomas Möller, Smita Saxena, Cristiane A M Moreno, Giancarlo Costaguta, Kristel R van Eijk, Hemali Phatnani, Ammar Al-Chalabi, A Nazli Başak, Leonard H van den Berg, Orla Hardiman, John E Landers, Jesus S Mora, Karen E Morrison, Pamela J Shaw, Jan H Veldink, Samuel L Pfaff, Ofer Yizhar, Christina Gross, Robert H Brown, John M Ravits, Matthew B Harms, Timothy M Miller, Eran Hornstein

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

Original languageEnglish
JournalScience Translational Medicine
Volume11
Issue number523
DOIs
Publication statusPublished - 18 Dec 2019
Externally publishedYes

Bibliographical note

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Keywords

  • Amyotrophic Lateral Sclerosis/genetics
  • Animals
  • Ether-A-Go-Go Potassium Channels/genetics
  • Humans
  • Mice
  • MicroRNAs/genetics
  • Motor Neurons/metabolism
  • Neurons/metabolism
  • Neuropathology/methods

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