Research ArticleAmyotrophic Lateral Sclerosis

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

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Science Translational Medicine  18 Dec 2019:
Vol. 11, Issue 523, eaav5264
DOI: 10.1126/scitranslmed.aav5264

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A micro(RNA) contribution to ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motor neuron degeneration and consequent progressive paralysis. Recent data have shown that microRNA-218 (miR-218) is enriched in motor neurons. However, whether neuronal miR-218 is modulated in ALS and plays a role in the disease is unknown. Now, Reichenstein et al. show that miR-218 controls neuronal activity by modulating the potassium channel Kv10.1 and its expression is reduced in motor neuron from patients with ALS. Screening of ALS genomes, the authors also identified miR-218 variants associated with reduced function, suggesting that this microRNA might play a role in ALS pathophysiology.

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.

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