International Journal of Molecular Sciences (May 2024)

Interaction between miR-142-3p and <i>BDNF</i> Val/Met Polymorphism Regulates Multiple Sclerosis Severity

  • Ettore Dolcetti,
  • Alessandra Musella,
  • Sara Balletta,
  • Luana Gilio,
  • Antonio Bruno,
  • Mario Stampanoni Bassi,
  • Gianluca Lauritano,
  • Fabio Buttari,
  • Diego Fresegna,
  • Alice Tartacca,
  • Fabrizio Mariani,
  • Federica Palmerio,
  • Valentina Rovella,
  • Rosangela Ferese,
  • Stefano Gambardella,
  • Emiliano Giardina,
  • Annamaria Finardi,
  • Roberto Furlan,
  • Georgia Mandolesi,
  • Diego Centonze,
  • Francesca De Vito

DOI
https://doi.org/10.3390/ijms25105253
Journal volume & issue
Vol. 25, no. 10
p. 5253

Abstract

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MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1β), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1β in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1β levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1β-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.

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