[Research Articles] Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

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.

Source: Science Translational Medicine - December 17, 2019 Category: Biomedical Science Authors: 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, Tags: Research Articles Source Type: research