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

Reichenstein, Irit; Eitan, Chen; Diaz-Garcia, Sandra; Haim, Guy; Magen, Iddo; Siany, Aviad; Hoye, Mariah L; Rivkin, Natali; Olender, Tsviya; Toth, Beata; Ravid, Revital; Mandelbaum, Amitai D; Yanowski, Eran; Liang, Jing; Rymer, Jeffrey K; Levy, Rivka; Beck, Gilad; Ainbinder, Elena; Farhan, Sali M K; Lennox, Kimberly A; ... (2019). Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology. Science translational medicine, 11(523) American Association for the Advancement of Science 10.1126/scitranslmed.aav5264

Text Reichenstein, 2019, Human genetics and neuropathology.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (2MB) | Request a copy

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.

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