Genome-wide circulating microRNA expression profiling reveals potential biomarkers for amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in TDP-43, FUS, and C9ORF72 are linked to amyotrophic lateral sclerosis (ALS), implicating RNA metabolism and microRNA (miRNA) dysregulation.
• ALS-associated proteins affect stress granule dynamics, influencing miRNA biogenesis and cellular levels.
• miRNAs in biological fluids are explored as potential ALS biomarkers.

Purpose of the Study:

• To identify and validate circulating miRNAs as potential biomarkers for amyotrophic lateral sclerosis (ALS).
• To investigate the expression profile of miRNAs in serum from ALS mouse models and human patients.
• To explore the relationship between specific miRNAs and ALS functional status and pathogenesis.

Main Methods:

• Next-generation sequencing (NGS) for comparative analysis of circulating miRNA expression in mutant SOD1 mice.
• Quantitative real-time polymerase chain reaction (qRT-PCR) for validation of candidate miRNAs.
• Analysis of serum samples from sporadic ALS patients and bioinformatics analysis of miRNA regulatory networks.

Main Results:

• NGS identified significant changes in 6 miRNAs in mutant SOD1 mice, with one also altered in mutant TDP-43 mice.
• Sporadic ALS patients showed significant deregulation of hsa-miR-142-3p and hsa-miR-1249-3p in serum.
• A negative correlation was found between ALS functional rating scale and hsa-miR-142-3p levels; bioinformatics suggested TDP-43 and C9ORF72 as targets.

Conclusions:

• Circulating miRNAs, particularly hsa-miR-142-3p and hsa-miR-1249-3p, are significantly altered in ALS patients.
• These identified miRNAs represent promising candidates for developing novel, non-invasive biomarkers for ALS diagnosis and monitoring.
• The findings suggest a potential role for hsa-miR-142-3p in ALS pathogenesis through regulation of key genes like TDP-43 and C9ORF72.