An miRNA fingerprint using neural-enriched extracellular vesicles from blood plasma: towards a biomarker for amyotrophic lateral sclerosis/motor neuron disease

Abstract

<jats:p>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.</jats:p>

A longitudinal study defined circulating microRNAs as reliable biomarkers for disease prognosis and progression in ALS human patients

“…Mir-199a has been described dyseregulated during microglial hyper-activation and persistent neuroinflammation, two abnormal conditions that support pathogenensis of ALS. In addition miR-151a-5p is thought to participate in the maintenance of cell viability in response to oxidative stress, its expression levels increased in the spinal cord of ALS patients, and it has been used as a non-muscle therapeutic target in ALS SOD1 G93A mouse models 13,29 . Interestingly, we observed the up-regulation of miR-151a-5p in the early phases of the disease and its significant down-modulation in the latest one, suggesting its involvement in the initial cell attempts to counteract disease onset and progression.…”

Exosomes: Innocent Bystanders or Critical Culprits in Neurodegenerative Diseases

“…Huntington's disease Alzheimer's disease Parkinson's disease Amyotrophic lateral sclerosis "Non-specific" exosomes Absence of mHTT (Denis et al, 2018) Phosphorylated tau (Saman et al, 2012) ↓REST (Goetzl et al, 2015) ↑miR195 and miR24 ↓miR19b (Cao et al, 2017) Altered levels of miRNA (Yelick et al, 2020) NDEs ↑Aβ1-42 ↓Synaptic proteins ↑TDP43 (Fiandaca et al, 2015;Goetzl et al, 2016Goetzl et al, , 2018Zhang et al, 2020) ↓synaptophysin, synaptotagmin and SNAP-25 (Goetzl et al, 2016;Agliardi et al, 2019) ↓miR132 and miR-212 (Walsh et al, 2019) ↑DJ1 and α-synuclein (Zhao et al, 2019) ↑α-synuclein and clusterin (Jiang et al, 2020) ↑α-synuclein (Shi et al, 2014;Jiang et al, 2020;Fu et al, 2020;Niu et al, 2020) Altered levels of miRNA (Katsu et al, 2019;Banack et al, 2020) NDEs, neuronally derived exosomes; mHTT, mutant huntingtin; REST, repressor element 1-silencing transcription factor; Aβ1-42, amyloid beta-42; TDP43, TAR DNAbinding protein 43; SNAP-25, 25 kD synaptosomal protein; miR, micro RNA.…”

“…The identification of miRNA (e.g., miR-124-3p, hsa-miR-4736, and miR-146a-5p) with altered levels in both neuronal-derived and total exosomes from ALS patients (CSF and plasma) gave some insight into novel targets to overcome the pathology ( Table 1 ; Banack et al, 2020 ). Nonetheless, the research regarding the role of exosome vesicles in ALS has still a long way to go to allow a better understanding of how we can use the already acquired knowledge to mitigate the progression of these neurodegenerative processes.…”

Secreted Extracellular Vesicle Molecular Cargo as a Novel Liquid Biopsy Diagnostics of Central Nervous System Diseases

“…For instance, in a recent study by Ebrahimkhani S. et al, the utility of serum exosome miRs as disease biomarkers of MS patients under treatment with fingolimod was assessed, and they found that several combinations of two or three miRNAs could discriminate active from quiescent disease with more than 90% accuracy [ 79 ]. Likewise, for ALS, Banack et al found that eight miRNAs, isolated from neural-enriched EVs, significantly distinguished ALS patients from controls, and thus might assist in early diagnosis of this disease [ 75 ].…”