Emerging role of microRNAs in the pathogenesis of amyotrophic lateral sclerosis

Dilmaghani, Nader Akbari; Hussen, Bashdar Mahmud; Nateghinia, Saeedeh; Taheri, Mohammad; Ghafouri‐Fard, Soudeh

doi:10.1007/s11011-021-00697-5

Cited by 12 publications

(11 citation statements)

References 48 publications

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“…We also identified a subset of DEmiRNAs in EVs that overlap between serum and CNS tissue, and uncovered signaling pathways associated with the predicted targets of the identified DEmiRNAs across tissues. As increasing evidence supports the contention that dysregulated miRNAs exert important functions in disease pathology (Paez-Colasante et al, 2015;Wang and Zhang, 2020;Akbari Dilmaghani et al, 2021), these results suggest a role of miRNA cargo from circulating EVs in ALS pathogenesis and also highlight the potential ability of EVs to serve as ALS biomarkers.…”

Section: Discussionsupporting

confidence: 59%

“…These small non-coding RNAs regulate gene expression posttranscriptionally by destabilizing multiple target mRNAs and thereby modulate physiological and pathological processes. Importantly, the presence of dysregulated miRNAs in ALS biofluids and postmortem tissue across multiple studies supports the contention that miRNAs exert important functions in disease pathology (Paez-Colasante et al, 2015;Wang and Zhang, 2020;Akbari Dilmaghani et al, 2021). Results from the current study provide a foundation for leveraging miRNA cargo from circulating EVs as a reflection of pathological EV signatures in ALS CNS tissue, generating new insight into possible pathogenic factors and untapped diagnostic opportunities.…”

Section: Introductionsupporting

confidence: 69%

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Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Figueroa‐Romero

Hur

et al. 2021

Front. Mol. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a terminalneurodegenerative 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 (EVs) 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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Section: Discussionsupporting

confidence: 59%

Section: Introductionsupporting

confidence: 69%

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Figueroa‐Romero

Hur

et al. 2021

Front. Mol. Neurosci.

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“…Bioinformatic analysis showed that these miRNAs regulate several genes associated with programmed cell death, synaptic plasticity and mitochondrial biogenesis, biological pathways/processes which well correlate with the disease pathogenesis [ 56 ]. Indeed, since miRNAs are fundamental for ensuring the physiological homeostasis of tissues, alterations in their expression profile can result in massive impairment of multiple biological pathways [ 57 – 59 ].…”

Section: Discussionmentioning

confidence: 99%

Insights into the identification of a molecular signature for amyotrophic lateral sclerosis exploiting integrated microRNA profiling of iPSC-derived motor neurons and exosomes

Melzi

Gagliardi

Resnati

et al. 2022

Cell. Mol. Life Sci.

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Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by progressive degeneration of motor neurons (MNs). Most cases are sporadic, whereas 10% are familial. The pathological mechanisms underlying the disease are partially understood, but it is increasingly being recognized that alterations in RNA metabolism and deregulation of microRNA (miRNA) expression occur in ALS. In this study, we performed miRNA expression profile analysis of iPSC-derived MNs and related exosomes from familial patients and healthy subjects. We identified dysregulation of miR-34a, miR-335 and miR-625-3p expression in both MNs and exosomes. These miRNAs regulate genes and pathways which correlate with disease pathogenesis, suggesting that studying miRNAs deregulation can contribute to deeply investigate the molecular mechanisms underlying the disease. We also assayed the expression profile of these miRNAs in the cerebrospinal fluid (CSF) of familial (fALS) and sporadic patients (sALS) and we identified a significant dysregulation of miR-34a-3p and miR-625-3p levels in ALS compared to controls. Taken together, all these findings suggest that miRNA analysis simultaneously performed in different human biological samples could represent a promising molecular tool to understand the etiopathogenesis of ALS and to develop new potential miRNA-based strategies in this new propitious therapeutic era.

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“…Thus, this study aimed to explore circulating disease-specific markers that would be beneficial for diagnosis and treatment strategies in ALS. By targeting multiple transcripts and affecting the expression of numerous proteins, miRNAs play a crucial role in cellular functions 36 . Researches in miRNA expression patterns and high-throughput profiling have resulted in exploring novel biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Identification of let-7f and miR-338 as plasma-based biomarkers for sporadic amyotrophic lateral sclerosis using meta-analysis and empirical validation

Daneshafrooz

Joghataei

Mehdizadeh

et al. 2022

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that in most cases occurs sporadic (sALS). The disease is not curable, and its pathogenesis mechanisms are not well understood yet. Given the intricacy of underlying molecular interactions and heterogeneity of ALS, the discovery of molecules contributing to disease onset and progression will open a new avenue for advancement in early diagnosis and therapeutic intervention. Here we conducted a meta-analysis of 12 circulating miRNA profiling studies using the robust rank aggregation (RRA) method, followed by enrichment analysis and experimental verification. We identified miR-451a and let-7f-5p as meta-signature miRNAs whose targets are involved in critical pathogenic pathways underlying ALS, including ‘FoxO signaling pathway’, ‘MAPK signaling pathway’, and ‘apoptosis’. A systematic review of 7 circulating gene profiling studies elucidated that 241 genes up-regulated in sALS circulation with concomitant being targets of the meta-signature miRNAs. Protein–protein interaction (PPI) network analysis of the candidate targets using MCODE algorithm revealed the main subcluster is involved in multiple cascades eventually leads apoptosis, including ‘positive regulation of neuron apoptosis. Besides, we validated the meta-analysis results using RT-qPCR. Indeed, relative expression analysis verified let-7f-5p and miR-338-3p as significantly down-regulated and up-regulated biomarkers in the plasma of sALS patients, respectively. Receiver operating characteristic (ROC) analysis also highlighted the let-7f-5p and miR-338-3p potential as robustness plasma biomarkers for diagnosis and potential therapeutic targets of sALS disease.

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Emerging role of microRNAs in the pathogenesis of amyotrophic lateral sclerosis

Cited by 12 publications

References 48 publications

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Insights into the identification of a molecular signature for amyotrophic lateral sclerosis exploiting integrated microRNA profiling of iPSC-derived motor neurons and exosomes

Identification of let-7f and miR-338 as plasma-based biomarkers for sporadic amyotrophic lateral sclerosis using meta-analysis and empirical validation

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