| Literature DB >> 31852800 |
Irit Reichenstein1, Chen Eitan1,2, Sandra Diaz-Garcia3, Guy Haim1, Iddo Magen1, Aviad Siany1, Mariah L Hoye4, Natali Rivkin1, Tsviya Olender1, Beata Toth1, Revital Ravid1, Amitai D Mandelbaum1, Eran Yanowski1, Jing Liang1, Jeffrey K Rymer5,6, Rivka Levy7, Gilad Beck8, Elena Ainbinder8, Sali M K Farhan9,10, Kimberly A Lennox11, Nicole M Bode11, Mark A Behlke11, Thomas Möller12, Smita Saxena13,14, Cristiane A M Moreno15, Giancarlo Costaguta16, Kristel R van Eijk2,17, Hemali Phatnani18, Ammar Al-Chalabi2,19,20, A Nazli Başak2,21, Leonard H van den Berg2,17, Orla Hardiman2,22,23, John E Landers2,24, Jesus S Mora2,25, Karen E Morrison2,26, Pamela J Shaw2,27, Jan H Veldink2,17, Samuel L Pfaff16, Ofer Yizhar7, Christina Gross5,6, Robert H Brown28, John M Ravits3, Matthew B Harms15, Timothy M Miller4, Eran Hornstein29,2.
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.Entities:
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Year: 2019 PMID： 31852800 PMCID： PMC7057809 DOI： 10.1126/scitranslmed.aav5264
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956