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GLAST-positive small extracellular-vesicle small RNA sequencing in amyotrophic lateral sclerosis: a paired 60-participant discovery cohort

ABSTRACT: Small-RNA sequencing of a plasma-derived, GLAST-positive small extracellular-vesicle fraction was performed in a discovery cohort of 60 participants, including 45 participants with amyotrophic lateral sclerosis (ALS) and 15 non-neurological controls. One small-RNA sequencing library was generated per participant using the QIAseq miRNA Library Kit and sequenced on an Illumina NovaSeq 6000 at the Yale Center for Genome Analysis. This Series contains the miRNA-seq data. Matched total-RNA sequencing was performed from the same vesicle RNA eluate and is deposited in a companion GEO Series. The data were generated to characterize extracellular-vesicle RNA cargo and identify molecular features associated with ALS and clinical progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE346895 | GEO | 2026/09/10

REPOSITORIES: GEO

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Project description:Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease. Clinical and molecular observations suggest that ALS pathology originates at a single site and spreads in an organized and prion-like manner, possibly driven by extracellular vesicles. Extracellular vesicles transfer cargo molecules associated with ALS pathogenesis, such as misfolded and aggregated proteins and dysregulated microRNAs (miRNAs). However, it is poorly understood whether altered levels of circulating extracellular vesicles or their cargo components reflect pathological signatures of the disease. In this study, we used immuno-affinity-based microfluidic technology, electron microscopy, and NanoString miRNA profiling to isolate and characterize extracellular vesicles and their miRNA cargo from frontal cortex, spinal cord, and serum of sporadic ALS (n=15) and healthy control (n=16) participants. We found larger extracellular vesicles in ALS spinal cord versus controls and smaller sized vesicles in ALS serum. However, there were no changes in the number of extracellular vesicles between cases and controls across any tissues. Characterization of extracellular vesicle-derived miRNA cargo in ALS compared to controls identified significantly altered miRNA levels in all tissues; miRNAs were reduced in ALS frontal cortex and spinal cord and increased in serum. Two miRNAs were dysregulated in all three tissues: miR-342-3p was increased in ALS, and miR-1254 was reduced in ALS. Additional miRNAs overlapping across two tissues included miR-587, miR-298, miR-4443, and miR-450a-2-3p. Predicted targets and pathways associated with the dysregulated miRNAs across the ALS tissues were associated with common biological pathways altered in neurodegeneration, including axon guidance and long-term potentiation. A predicted target of one identified miRNA (N-deacetylase and N-sulfotransferase 4; NDST4) was likewise dysregulated in an in vitro model of ALS, verifying potential biological relevance. Together, these findings demonstrate that circulating extracellular vesicle miRNA cargo mirror those of the central nervous system disease state in ALS, and thereby offer insight into possible pathogenic factors and diagnostic opportunities.

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GLAST-positive small extracellular-vesicle small RNA sequencing in amyotrophic lateral sclerosis: a paired 60-participant discovery cohort

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