Aim 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). Methods and Results In a cohort of 151 MS patients, we found positive correlations between CSF miR-142-3p levels and clinical progression, IL-1 beta 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. Conclusion MiR-142-3p is a novel and potential negative prognostic CSF marker of MS and a promising tool for identifying personalised therapies.

De Vito, F., Musella, A., Fresegna, D., Rizzo, F.R., Gentile, A., Stampanoni Bassi, M., et al. (2021). MiR-142-3p regulates synaptopathy-driven disease progression in multiple sclerosis. NEUROPATHOLOGY & APPLIED NEUROBIOLOGY [10.1111/nan.12765].

MiR-142-3p regulates synaptopathy-driven disease progression in multiple sclerosis

Musella, Alessandra;Fresegna, Diego;Rizzo, Francesca Romana;Gentile, Antonietta;Buttari, Fabio;Bullitta, Silvia;Caioli, Silvia;Vanni, Valentina;Bruno, Antonio;Centonze, Diego;
2021-09-07

Abstract

Aim 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). Methods and Results In a cohort of 151 MS patients, we found positive correlations between CSF miR-142-3p levels and clinical progression, IL-1 beta 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. Conclusion MiR-142-3p is a novel and potential negative prognostic CSF marker of MS and a promising tool for identifying personalised therapies.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/26
eng
Con Impact Factor ISI
biological marker
experimental autoimmune encephalomyelitis
fumarates
microRNA
multiple sclerosis
synaptopathy
https://onlinelibrary.wiley.com/doi/epdf/10.1111/nan.12765
De Vito, F., Musella, A., Fresegna, D., Rizzo, F.R., Gentile, A., Stampanoni Bassi, M., et al. (2021). MiR-142-3p regulates synaptopathy-driven disease progression in multiple sclerosis. NEUROPATHOLOGY & APPLIED NEUROBIOLOGY [10.1111/nan.12765].
De Vito, F; Musella, A; Fresegna, D; Rizzo, Fr; Gentile, A; Stampanoni Bassi, M; Gilio, L; Buttari, F; Procaccini, C; Colamatteo, A; Bullitta, S; Guadalupi, L; Caioli, S; Vanni, V; Balletta, S; Sanna, K; Bruno, A; Dolcetti, E; Furlan, R; Finardi, A; Licursi, V; Drulovic, J; Pekmezovic, T; Fusco, C; Bruzzaniti, S; Hornstein, E; Uccelli, A; Salvetti, M; Matarese, G; Centonze, D; Mandolesi, G
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/282255
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