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Deregulation of Plasma microRNA Expression in a TARDBP-ALS Family
Paola Ruffo1,2, Stefania Catalano3, Vincenzo La Bella4
1Medical Genetics Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
Abstract:
TDP-43 intracellular aggregates are a pathogenic sign of most amyotrophic lateral sclerosis (ALS) cases. Familial ALS, brought on by TARDBP gene mutations, emphasizes the relevance of this altered protein in pathophysiology. Growing evidence suggests a role for dysregulated microRNA (miRNA) in ALS disease. Furthermore, several studies showed that miRNAs are highly stable in various biological fluids (CSF, blood, plasma, and serum), and they are expressed differentially by comparing ALS patients and controls. In 2011, our research group discovered a rare mutation in a TARDBP gene (G376D) in a large ALS Apulian family with affected members exhibiting a rapidly progressing disease. To identify potential non-invasive biomarkers of preclinical and clinical progression in the TARDBP-ALS family, we assessed the expression levels of plasma microRNAs in affected patients (n = 7) and asymptomatic mutation carriers (n = 7) compared with healthy controls (n = 13). Applying qPCR, we investigate 10 miRNAs that bind TDP-43 in vitro during their biogenesis or in their mature form, and the other nine are known to be deregulated in the disease. We highlight the potential of miR-132-5p, miR-132-3p, miR-124-3p, and miR-133a-3p expression levels in plasma as biomarkers of preclinical progression for G376D-TARDBP-associated ALS. Our research strongly supports the potential of plasma miRNAs as biomarkers for performing predictive diagnostics and identifying new therapeutic targets.
Insights
Plasma microRNAs (miRNAs) show promise as biomarkers for amyotrophic lateral sclerosis (ALS). Specific miRNAs, including miR-132-5p, can detect preclinical progression in familial ALS linked to TARDBP mutations.
Area of Science:
- Neuroscience
- Genetics
- Biomarker Discovery
Background:
- Intracellular aggregates of TDP-43 protein are a hallmark of most amyotrophic lateral sclerosis (ALS) cases.
- Mutations in the TARDBP gene are linked to familial ALS, underscoring TDP-43's role in the disease.
- Dysregulated microRNAs (miRNAs) are increasingly implicated in ALS pathogenesis and are detectable in biological fluids.
Purpose of the Study:
- To identify non-invasive plasma microRNA biomarkers for preclinical and clinical progression in a family with G376D-TARDBP-associated ALS.
- To assess plasma miRNA expression levels in ALS patients, asymptomatic mutation carriers, and healthy controls.
Main Methods:
- Quantitative PCR (qPCR) was used to measure the expression levels of 19 specific plasma miRNAs.
- These miRNAs were selected based on their interaction with TDP-43 or known deregulation in ALS.
- Plasma samples were analyzed from 7 affected ALS patients, 7 asymptomatic TARDBP mutation carriers, and 13 healthy controls.
Main Results:
- Expression levels of miR-132-5p, miR-132-3p, miR-124-3p, and miR-133a-3p in plasma were highlighted as potential biomarkers.
- These specific miRNAs showed potential for indicating preclinical progression in individuals with the G376D-TARDBP mutation.
Conclusions:
- Plasma microRNAs demonstrate significant potential as non-invasive biomarkers for predictive diagnostics in G376D-TARDBP-associated ALS.
- The findings support the utility of plasma miRNAs for early detection and potentially identifying novel therapeutic targets for ALS.
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