MiR-142-3p is a Critical Modulator of TNF-mediated Neuronal Toxicity in Multiple Sclerosis

Francesca De Vito, Sara Balletta, Silvia Caioli, Alessandra Musella, Livia Guadalupi, Valentina Vanni, Diego Fresegna, Mario Stampanoni Bassi, Luana Gilio, Krizia Sanna, Antonietta Gentile, Antonio Bruno, Ettore Dolcetti, Fabio Buttari, Luigi Pavone, Roberto Furlan, Annamaria Finardi, Emerald Perlas, Eran Hornstein, Diego CentonzeGeorgia Mandolesi

Research output: Contribution to journalArticlepeer-review


Background: TNF-dependent synaptotoxicity contributes to the neuronal damage occurring in patients with Multiple Sclerosis (pwMS) and its mouse model Experimental Autoimmune Encephalomyelitis (EAE). Here, we investigated miR-142-3p, a synaptotoxic microRNA induced by inflammation in EAE and MS, as a potential downstream effector of TNF signalling. Methods: Electrophysiological recordings, supported by molecular, biochemical and histochemical analyses, were performed to explore TNF-synaptotoxicity in the striatum of EAE and healthy mice. MiR-142 heterozygous (miR-142 HE) mice and/or LNA-anti miR-142-3p strategy were used to verify the TNF-miR-142-3p axis hypothesis. The cerebrospinal fluid (CSF) of 151 pwMS was analysed to evaluate possible correlation between TNF and miR-142-3p levels and their impact on clinical parameters (e.g. progression index (PI), age-related clinical severity (gARMSS)) and MRI measurements at diagnosis (T0). Results: High levels of TNF and miR-142-3p were detected in both EAE striatum and MS-CSF. The TNF-dependent glutamatergic alterations were prevented in the inflamed striatum of EAE miR-142 HE mice. Accordingly, TNF was ineffective in healthy striatal slices incubated with LNA-anti miR142-3p. However, both preclinical and clinical data did not validate the TNF-miR-142-3p axis hypothesis, suggesting a permissive neuronal role of miR-142-3p on TNF-signalling. Clinical data showed a negative impact of each molecule on disease course and/or brain lesions and unveiled that their high levels exert a detrimental synergistic effect on disease activity, PI and white matter lesion volume. Conclusion: We propose miR-142-3p as a critical modulator of TNF-mediated neuronal toxicity and suggest a detrimental synergistic action of these molecules on MS pathology.

Original languageEnglish
Pages (from-to)2567-2582
Number of pages16
JournalCurrent Neuropharmacology
Issue number12
StatePublished - 5 Apr 2023

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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