Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Magen, Iddo; Coenen-Stass, Anna M.L.; Großkreutz, Julian; Lu, Ching‐Hua; Greensmith, Linda; Malaspina, Andrea; Fratta, Pietro; Hornstein, Eran

doi:10.1101/833079

Cited by 4 publications

(5 citation statements)

References 49 publications

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“…ALS patients with high plasma levels of miR‐181 were almost five times more likely to die during the study period in a multivariate model inclusive of previously established prognostic markers. 77 When blood measurement of miR‐181 was combined with that of NfL, the prognostic performance in ALS was even stronger. 77 , 89 …”

Section: Utilisation Of Blood Biomarkers In Alsmentioning

confidence: 99%

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Blood biomarkers in ALS : challenges, applications and novel frontiers

Sturmey

Malaspina

2022

Acta Neuro Scandinavica

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Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease among adults. With diagnosis reached relatively late into the disease process, extensive motor cell loss narrows the window for therapeutic opportunities. Clinical heterogeneity in ALS and the lack of disease‐specific biomarkers have so far led to large‐sized clinical trials with long follow‐up needed to define clinical outcomes. In advanced ALS patients, there is presently limited scope to use imaging or invasive cerebrospinal fluid (CSF) collection as a source of disease biomarkers. The development of more patient‐friendly and accessible blood biomarker assays is hampered by analytical hurdles like the matrix effect of blood components. However, blood also provides the opportunity to identify disease‐specific adaptive changes of the stoichiometry and conformation of target proteins and the endogenous immunological response to low‐abundance brain peptides, such as neurofilaments (Nf). Among those biomarkers under investigation in ALS, the change in concentration before or after diagnosis of Nf has been shown to aid prognostication and to allow the a priori stratification of ALS patients into smaller sized and clinically more homogeneous cohorts, supporting more affordable clinical trials. Here, we discuss the technical hurdles affecting reproducible and sensitive biomarker measurement in blood. We also summarize the state of the art of non‐CSF biomarkers in the study of prognosis, disease progression, and treatment response. We will then address the potential as disease‐specific biomarkers of the newly discovered cryptic peptides which are formed down‐stream of TDP‐43 loss of function, the hallmark of ALS pathobiology.

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Section: Utilisation Of Blood Biomarkers In Alsmentioning

confidence: 99%

“… 77 When blood measurement of miR‐181 was combined with that of NfL, the prognostic performance in ALS was even stronger. 77 , 89 …”

Section: Utilisation Of Blood Biomarkers In Alsmentioning

confidence: 99%

Blood biomarkers in ALS : challenges, applications and novel frontiers

Sturmey

Malaspina

2022

Acta Neuro Scandinavica

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“…microRNAs (miRNAs), endogenous non-coding RNAs, can be quantified in biofluids (18), and have been shown previously to be dysregulated in amyotrophic lateral sclerosis (ALS) and in FTD (19). Furthermore, they may be biomarkers of disease progression in other brain diseases, including ALS (20). Previous studies have assessed the initial potential of microRNAs as diagnostic FTD biomarkers including miRNA analysis in plasma (21)(22)(23), CSF and serum (24), and CSF exosomes (25) but no definitive markers have so far been found.…”

Section: Introductionmentioning

confidence: 99%

microRNA-based predictor for diagnosis of frontotemporal dementia

Magen

Warren

Heller

et al. 2020

Preprint

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Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by frontal and temporal lobe atrophy, typically manifesting with behavioural or language impairment. Because of its heterogeneity and lack of available diagnostic laboratory tests there can be a substantial delay in diagnosis. Cell-free, circulating, microRNAs are increasingly investigated as biomarkers for neurodegeneration, but their value in FTD is not yet established. In this study, we investigate microRNAs as biomarkers for FTD diagnosis. We performed next generation small RNA sequencing on cell-free plasma from 52 FTD cases and 21 controls. The analysis revealed the diagnostic importance of 20 circulating endogenous miRNAs in distinguishing FTD cases from controls. The study was repeated in an independent second cohort of 117 FTD cases and 35 controls. The combinatorial microRNA signature from the first cohort, precisely diagnosed FTD samples in a second cohort. To further increase the generalizability of the prediction, we implemented machine learning techniques in a merged dataset of the two cohorts, which resulted in a comparable or improved classification precision with a smaller panel of miRNA classifiers. In addition, there are intriguing molecular commonalities with cell free miRNA signature in ALS, a motor neuron disease that resides on a pathological continuum with FTD. However, the signature that describes the ALS-FTD spectrum is not shared with blood miRNA profiles of patients with multiple sclerosis. Thus, microRNAs are promising FTD biomarkers that might enable earlier detection of FTD and improve accurate identification of patients for clinical trials

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“…Interestingly, in this study we identify miR-181a-5p as a potential human biomarker of FTSJ1 activity. Fortunately, this study was performed on LCLs that are derived from the blood of patients and miR-181a-5p is reported to be circulant in human bloodstream (Magen et al 2019). Thus, in the longer term, we hope to characterize accumulation of miR-181a-5p in crude blood samples or plasma cell-free of ID patients carrying a FTSJ1 mutation to facilitate the diagnosis of ID-FTSJ1 patients.…”

Section: Discussionmentioning

confidence: 99%

The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance

Dimitrova

Brazane

Pigeon

et al. 2021

Preprint

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FTSJ1 is a phyllogenetically conserved human 2-O-methyltransferase (Nm-MTase) which modifies position 32 as well as the wobble position 34 in the AntiCodon Loop (ACL) of specific tRNAs: tRNAPhe(GAA), tRNATrp(CCA) and tRNALeu(UAA). FTSJ1 loss of function has been linked to Non-Syndromic X-Linked Intellectual Disability (NSXLID), and more recently in cancers. However, the exact molecular mechanisms underlying FTSJ1-related pathogenesis are unknown and a potential extended variety of FTSJ1 tRNA targets has not been fully addressed yet. We performed unbiased and comprehensive RiboMethSeq analysis of the Nm profiles for human tRNA population extracted from cells derived from NSXLID patients blood bearing various characterized loss of function mutations in FTSJ1. In addition, we reported a novel FTSJ1 pathogenic variant from a NSXLID patient bearing a de novo mutation in the FTSJ1 gene. Some of the newly identified FTSJ1 tRNA targets are also conserved in Drosophila as shown by our previous study on the fly homologues Trm7_32 and Trm7_34, whose loss affects small RNA silencing pathways. In the current study, we reveal a conserved deregulation in both the miRNA and mRNA populations when FTSJ1 function is compromised. In addition, a cross-analysing between deregulated miRNA and mRNA obtained in FTSJ1 mutants highlighted upregulation of miR10a-5p which has the capacity to silence the SPARC gene mRNA, downregulated in FTSJ1 mutant cells. This suggests that FTSJ1 loss may influence gene expression deregulation by modulation of miRNA silencing. A gene-ontology (GO) enrichment analysis of the deregulated mRNAs primarily matched to brain morphogenesis terms, followed by metabolism and translation related genes. In parallel, the deregulated miRNAs are mostly known for their implication in brain functions and cancers. Based on these results, we suggest that miRNA silencing variations may play a role in the pathological mechanisms of FTSJ1-dependent NSXLID. Finally, our results highlight miR-181a-5p as a potential companion diagnostic test in clinical settings for FTSJ1-related intellectual disability.

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Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Cited by 4 publications

References 49 publications

Blood biomarkers in ALS : challenges, applications and novel frontiers

Blood biomarkers in ALS : challenges, applications and novel frontiers

microRNA-based predictor for diagnosis of frontotemporal dementia

The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance

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