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.

中文翻译：

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人类遗传学和神经病理学表明 miR-218 与肌萎缩侧索硬化症病理生理学之间存在联系。

运动神经元特异性 microRNA-218 (miR-218) 最近因其在小鼠发育中的作用而受到关注。然而，尚未探索 miR-218 与人类运动神经元疾病的相关性。在这里，我们通过神经病理学证明 miR-218 在健康的人类运动神经元中含量丰富。然而，在肌萎缩侧索硬化症 (ALS) 运动神经元中，miR-218 被下调，其 mRNA 靶标相互上调（去抑制）。我们进一步将钾通道 Kv10.1 确定为控制神经元活动的新 miR-218 直接靶标。此外，我们筛选了数千个 ALS 基因组，并在人类 miR-218-2 序列中鉴定了六种罕见变体。miR-218 基因变异不能调节神经元活动，表明这种小的内源性 RNA 对神经元稳健性的重要性。潜在机制涉及抑制 miR-218 生物发生和减少 DICER 的加工。因此，运动神经元中的 miR-218 活性可能易受人类 ALS 衰竭的影响，这表明 miR-218 可能是运动神经元疾病的潜在治疗靶点。