1. Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology
- Author
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Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Reichenstein,I.; Eitan, C.; Diaz-Garcia, S.; Haim, G.; Magen, I.; Siany, A.; Hoye, M.L.; Rivkin, N.; Olender, T.; Toth, B.; Ravid, R.; Mandelbaum, A.D.; Yanowski, E.; Liang, J.; Rymer, J.K.; Levy, R.; Beck, G.; Ainbinder, E.; Farhan,S.M.K.; Lennox, K.A.; Bode, N.M.; Behlke, M.A.; Möller, T.; Saxena, S.; Moreno, C.A.M.; Costaguta, G.; van Eijk, K.R.; Phatnani, H.; Al-Chalabi, A.; van den Berg, L.H.; Hardiman, O.; Landers, J.E.; Mora, J.S.; Morrison, K.E.; Shaw, P.J.; Veldink, J.H.; Pfaff S.L.; Yizhar, O.; Gross, C.; Brown, R.H. Jr.; Ravits, J.M.; Harms, M.B.; Miller, T.M.; Hornstein, E., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Reichenstein,I.; Eitan, C.; Diaz-Garcia, S.; Haim, G.; Magen, I.; Siany, A.; Hoye, M.L.; Rivkin, N.; Olender, T.; Toth, B.; Ravid, R.; Mandelbaum, A.D.; Yanowski, E.; Liang, J.; Rymer, J.K.; Levy, R.; Beck, G.; Ainbinder, E.; Farhan,S.M.K.; Lennox, K.A.; Bode, N.M.; Behlke, M.A.; Möller, T.; Saxena, S.; Moreno, C.A.M.; Costaguta, G.; van Eijk, K.R.; Phatnani, H.; Al-Chalabi, A.; van den Berg, L.H.; Hardiman, O.; Landers, J.E.; Mora, J.S.; Morrison, K.E.; Shaw, P.J.; Veldink, J.H.; Pfaff S.L.; Yizhar, O.; Gross, C.; Brown, R.H. Jr.; Ravits, J.M.; Harms, M.B.; Miller, T.M.; Hornstein, E., and Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM)
- 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., Target ALS; European Union (European Union); Horizon 2020; European Research Council (ERC), European Union's Seventh Framework Programme (FP7/2007-2013); AFM Telethon; NIH; National Institute of Neurological Disorders and Stroke; NIH/NINDS; United Kingdom, Medical Research Council; Suna and İnan Kıraç Foundation; Legacy Heritage Fund; Bruno and Ilse Frick Foundation for Research on ALS; Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE); Minna-James-Heineman Stiftung through Minerva; Israel Science Foundation; ALS-Therapy Alliance; Motor Neuron Disease Association (United Kingdom); Thierry Latran Foundation for ALS research; ERA-Net for Research Programmes on Rare Diseases (FP7); IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (United Kingdom); ALS Canada Tim E. Noel Postdoctoral Fellowship; Project5 for ALS; Robert Packard Center for ALS Research; University of Missouri Spinal Cord Injury/Disease Research Program; Hope Center for Neurological Disorders; ALS Association ; Biogen; ALS Finding a Cure; Angel Fund; ALS-One; Cellucci Fund; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre
- Published
- 2019