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

Authors: Irit Reichenstein, Chen Eitan, Sandra Díaz-García, Guy Haim, Iddo Magen, Aviad Siany, Mariah L. Hoye, Natali Rivkin, Tsviya Olender, Beáta Tóth, Revital Ravid, Amitai D. Mandelbaum, Eran Yanowski, Jing Liang, Jeffrey K. Rymer, Rivka Levy, Gilad Beck, Elena Ainbinder, Sali M.K. Farhan, Kimberly A. Lennox, Nicole M. Bode, Mark A. Behlke, Thomas Möller, Smita Saxena, Cristiane Araújo Martins Moreno, Giancarlo Costaguta, Kristel R. van Eijk, Hemali Phatnani, Ammar Al‐Chalabi, A. Nazlı Başak, Leonard H. van den Berg, Orla Hardiman, John E. Landers, Jesús S. Mora, Karen Morrison, Pamela J. Shaw, Jan H. Veldink, Samuel L. Pfaff, Ofer Yizhar, Christina Groß, Robert H. Brown, John Ravits, Matthew Harms, Timothy M. Miller, Eran Hornstein - Science Translational Medicine 2019 cited by 62

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.