In:
Current Neuropharmacology, Bentham Science Publishers Ltd., Vol. 21, No. 12 ( 2023-12), p. 2567-2582
Abstract:
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 miR-
142-3p. 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.
Type of Medium:
Online Resource
ISSN:
1570-159X
DOI:
10.2174/1570159X21666230404103914
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2023
detail.hit.zdb_id:
2119376-9
