title: miR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation.
abstract: MicroRNAs (miRNA) play an important role in post-transcriptional gene regulation of several physiological and pathological processes. In multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the CNS, and in its mouse model, the experimental autoimmune encephalomyelitis (EAE), miRNA dysregulation has been mainly related to immune system dysfunction and white matter (WM) pathology. However, little is known about their role in gray matter pathology. Here, we explored miRNA involvement in the inflammation-driven alterations of synaptic structure and function, collectively known as synaptopathy, a neuropathological process contributing to excitotoxic neurodegeneration in MS/EAE. Particularly, we observed that miR-142-3p is increased in the CSF of patients with active MS and in EAE brains. We propose miR-142-3p as a molecular mediator of the IL-1β-dependent downregulation of the glial glutamate-aspartate transporter (GLAST), which causes an enhancement of the glutamatergic transmission in the EAE cerebellum. The synaptic abnormalities mediated by IL-1β and the clinical and neuropathological manifestations of EAE disappeared in miR-142 knock-out mice. Furthermore, we observed that in vivo miR-142-3p inhibition, either by a preventive and local treatment or by a therapeutic and systemic strategy, abolished IL-1β- and GLAST-dependent synaptopathy in EAE wild-type mice. Consistently, miR-142-3p was responsible for the glutamatergic synaptic alterations caused by CSF of patients with MS, and CSF levels of miR-142-3p correlated with prospective MS disease progression. Our findings highlight miR-142-3p as key molecular player in IL-1β-mediated synaptic dysfunction, possibly leading to excitotoxic damage in both EAE and MS diseases. Inhibition of miR-142-3p could be neuroprotective in MS.
  
  
  
  Current studies suggest the role of glutamate excitotoxicity in the development and progression of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE). The molecular mechanisms linking inflammation and synaptic alterations in MS/EAE are still unknown. Here, we identified miR-142-3p as a determinant molecular actor in inflammation-dependent synaptopathy typical of both MS and EAE. miR-142-3p was upregulated in the CSF of MS patients and in EAE cerebellum. Inhibition of miR-142-3p, locally in EAE brain and in a MS chimeric ex vivo model, recovered glutamatergic synaptic enhancement typical of EAE/MS. We proved that miR-142-3p promoted the IL-1β-dependent glutamate dysfunction by targeting glutamate-aspartate transporter (GLAST), a crucial glial transporter involved in glutamate homeostasis. Finally, we suggest miR-142-3p as a negative prognostic factor in patients with relapsing-remitting multiple sclerosis.
authors.affiliation: Centro Europeo per la Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy, g.mandolesi@hsantalucia.it.
authors.forename: Georgia
authors.initials: G
authors.lastname: Mandolesi
authors.affiliation: Centro Europeo per la Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.|Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Vito
authors.affiliation: Centro Europeo per la Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.affiliation: Centro Europeo per la Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.|Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Gentile
authors.affiliation: Centro Europeo per la Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bullitta
authors.affiliation: Centro Europeo per la Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.|Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Fresegna
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy.
authors.forename: Helena
authors.initials: H
authors.lastname: Sepman
authors.affiliation: Centro Europeo per la Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Di Sanza
authors.affiliation: Centro Europeo per la Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.|Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy.
authors.forename: Nabila
authors.initials: N
authors.lastname: Haji
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy.|Dipartimento di Neurologia, IRCCS Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mori
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy.|Dipartimento di Neurologia, IRCCS Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Buttari
authors.affiliation: European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo Scalo, 00015 Rome, Italy.
authors.forename: Emerald
authors.initials: E
authors.lastname: Perlas
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ciotti
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Hornstein
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin," Sapienza Università di Roma, Rome, 00185 Italy, and.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome 00161, Italy.
authors.forename: Irene
authors.identifier: 0000-0002-3485-8537
authors.initials: I
authors.lastname: Bozzoni
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin," Sapienza Università di Roma, Rome, 00185 Italy, and.
authors.forename: Carlo
authors.initials: C
authors.lastname: Presutti
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università degli Studi di Roma Tor Vergata, 00133 Rome, Italy.|Dipartimento di Neurologia, IRCCS Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis* / Q000134:cerebrospinal fluid; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
chemical_list: D053583:Interleukin-1beta; C555159:MIRN142 microRNA, human; D035683:MicroRNAs
keywords: CSF; experimental autoimmune encephalomyelitis; glial glutamate transporter; glutamate excitotoxicity; microRNA; multiple sclerosis