LncRNA levels in the central nervous system as novel potential players and biomarkers in amyotrophic lateral sclerosis

López-Royo, Tresa ; Moreno-Martínez, Laura (Universidad de Zaragoza) ; Rada, Gabriel (Universidad de Zaragoza) ; Macías-Redondo, Sofía ; Calvo, Ana Cristina (Universidad de Zaragoza) ; García-Redondo, Alberto ; Manzano, Raquel (Universidad de Zaragoza) ; Osta, Rosario (Universidad de Zaragoza)

Resumen: Research in amyotrophic lateral sclerosis (ALS) faces major burdens, including the urgent need for sensitive and specific biomarkers, the identification of novel and effective therapeutic targets and a deeper understanding of the mechanisms driving the disease. In this line, long non-coding RNAs (lncRNAs) have emerged as promising candidates due to their regulatory role in a variety of important biological processes such as RNA metabolism, neuroinflammation, apoptosis or proteostasis.
This study aims to elucidate the expression profile of 14 lncRNAs in both the SOD1G93A mouse model and ALS patients. Different stages of the disease (presymptomatic, symptomatic and terminal) and 3 regions of the central nervous system (CNS) differentially affected by ALS (spinal cord, brainstem and frontal cortex) were included in the experimental design.
In SOD1G93A mice, all 14 lncRNAs exhibited differential expression patterns influenced by sex, age, and region, except for Malat1, Neat1, and H19, which displayed consistent expression patterns (Malat1 was decreased, while Neat1 and H19 were increased). These patterns were most prominent in the spinal cord, where lncRNAs were overall down-regulated. In contrast, in the brainstem and frontal cortex, lncRNAs were predominantly up-regulated. Notably, Gas5 expression levels in frontal cortex and spinal cord at the terminal stage correlated with the onset and progression of motor coordination and strength decline. Additionally, three lncRNAs (Gas5, Neat1 and Myoparr) were found to significantly correlate with survival.
In human ALS samples, increased levels of NEAT1 and SNHG16 were observed in the brainstem, and of MEG3 and H19 in the frontal cortex, whereas MALAT1 levels were decreased in frontal cortex.
In conclusion, this work supports lncRNAs as promising candidates as novel players and potential biomarkers in ALS and highlights SOD1G93A mice as a good model to study lncRNAs in the CNS in the context of this disease.

Idioma: Inglés

DOI: 10.1016/j.ncrna.2025.05.017

Año: 2025

Publicado en: Non-coding RNA Research 14 (2025), 145-155
ISSN: 2468-0540

Financiación: info:eu-repo/grantAgreement/ES/DGA/A19-23R
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI21-00286
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CB18-05-0037
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FEDER/PI21-00372
Financiación: info:eu-repo/grantAgreement/ES/MCIU/FPU19-05625
Financiación: info:eu-repo/grantAgreement/ES/MICIU/PRTR-C17.I1

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Genética (Dpto. Anatom.,Embri.Genét.Ani.)
Área (Departamento): Área Farmacología (Dpto. Farmac.Fisiol.y Med.L.F.)