Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy.
Synaptic Immunopathology Lab, IRCCS San Raffaele Roma, Italy.
Neuropathol Appl Neurobiol. 2022 Feb;48(2):e12765. doi: 10.1111/nan.12765. Epub 2021 Oct 6.
We recently proposed miR-142-3p as a molecular player in inflammatory synaptopathy, a new pathogenic hallmark of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE), that leads to neuronal loss independently of demyelination. MiR-142-3p seems to be unique among potential biomarker candidates in MS, since it is an inflammatory miRNA playing a dual role in the immune and central nervous systems. Here, we aimed to verify the impact of miR-142-3p circulating in the cerebrospinal fluid (CSF) of MS patients on clinical parameters, neuronal excitability and its potential interaction with disease modifying therapies (DMTs).
In a cohort of 151 MS patients, we found positive correlations between CSF miR-142-3p levels and clinical progression, IL-1β signalling as well as synaptic excitability measured by transcranial magnetic stimulation. Furthermore, therapy response of patients with 'low miR-142-3p' to dimethyl fumarate (DMF), an established disease-modifying treatment (DMT), was superior to that of patients with 'high miR-142-3p' levels. Accordingly, the EAE clinical course of heterozygous miR-142 mice was ameliorated by peripheral DMF treatment with a greater impact relative to their wild type littermates. In addition, a central protective effect of this drug was observed following intracerebroventricular and ex vivo acute treatments of EAE wild type mice, showing a rescue of miR-142-3p-dependent glutamatergic alterations. By means of electrophysiology, molecular and biochemical analysis, we suggest miR-142-3p as a molecular target of DMF.
MiR-142-3p is a novel and potential negative prognostic CSF marker of MS and a promising tool for identifying personalised therapies.
我们最近提出 miR-142-3p 是炎症性突触病的分子参与者，这是多发性硬化症（MS）及其实验性自身免疫性脑脊髓炎（EAE）的新型致病标志，它导致神经元丢失而不依赖于脱髓鞘。miR-142-3p 在 MS 的潜在生物标志物候选物中似乎是独一无二的，因为它是一种在免疫系统和中枢神经系统中发挥双重作用的炎症 miRNA。在这里，我们旨在验证 MS 患者脑脊液（CSF）中循环的 miR-142-3p 对临床参数、神经元兴奋性及其与疾病修饰疗法（DMT）的潜在相互作用的影响。
在 151 名 MS 患者的队列中，我们发现 CSF miR-142-3p 水平与临床进展、IL-1β 信号以及经颅磁刺激测量的突触兴奋性之间呈正相关。此外，“低 miR-142-3p”患者对二甲基富马酸（DMF）的治疗反应（一种已确立的疾病修饰治疗（DMT））优于“高 miR-142-3p”水平的患者。相应地，杂合 miR-142 小鼠的 EAE 临床病程通过外周 DMF 治疗得到改善，与野生型同窝仔相比，影响更大。此外，在 EAE 野生型小鼠的脑室内和离体急性治疗中观察到该药物的中枢保护作用，表明其挽救了 miR-142-3p 依赖性谷氨酸能改变。通过电生理学、分子和生化分析，我们将 miR-142-3p 作为 DMF 的分子靶标。
miR-142-3p 是 MS 的新型潜在负预后 CSF 标志物，也是识别个性化治疗的有前途的工具。
