Abstract
Biomarkers for amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are currently not clinically available for disease diagnosis or analysis of disease progression. If identified, biomarkers could improve patient outcomes by enabling early intervention and assist in the determination of treatment efficacy. We hypothesized that neural-enriched extracellular vesicles could provide microRNA (miRNA) fingerprints with unequivocal signatures of neurodegeneration. Using blood plasma from ALS/MND patients and controls, we extracted neural-enriched extracellular vesicle fractions and conducted next-generation sequencing and qPCR of miRNA components of the transcriptome. We here report eight miRNA sequences which significantly distinguish ALS/MND patients from controls in a replicated experiment using a second cohort of patients and controls. miRNA sequences from patient blood samples using neural-enriched extracellular vesicles may yield unique insights into mechanisms of neurodegeneration and assist in early diagnosis of ALS/MND.
Highlights
Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) continue to provide challenges for diagnosis since validated, clinically useful diagnostic biomarkers are currently unavailable
In two separate experiments using a different cohort of patients and controls for each experiment, we found eight miRNA sequences that were significantly and consistently different between ALS/MND patients and healthy controls
We note that tumour susceptibility gene 101 (TSG101), a component of the endosomal sorting complexes required for transport (ESCRT-I) complex, which is common in exosomes, was present and that a marker of cell contamination, calnexin, was absent
Summary
Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) continue to provide challenges for diagnosis since validated, clinically useful diagnostic biomarkers are currently unavailable. The search for ALS/MND biomarkers useful for diagnosis, prognosis and analysis of drug efficacy includes a variety of molecules found in biofluids and other techniques including: heavy and light chain neurofilaments, TAR DNA-binding protein 43 (TDP-43), a lipid peroxidation product (4-hydroxy-2,3-nonenal), a urinary neurotrophin receptor p75 extracellular domain, cystatin C, mRNA, miRNA, extracellular glutamate, markers of inflammation, microglial activation, electrical impedance myography, rate of disease progression, spinal cord imaging and others [1,5,6,7,8,9,10,11,12,13,14,15,16,17]. None of these biomarkers have been sufficiently validated to be incorporated into the clinical standard of care [1,3,9,15,18]
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