Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Reichenstein, Irit; Eitan, Chen; Diaz-Garcia, Sandra; Haim, Guy; Magen, Iddo; Siany, Aviad; Hoye, Mariah L.; Rivkin, Natali; Olender, Tsviya; Tóth, Beáta; Ravid, Revital; Mandelbaum, Amitai D.; Yanowski, Eran; Liang, Jing; Rymer, Jeffrey K.; Levy, Rivka; Beck, Gilad; Ainbinder, Elena; Farhan, Sali M.K.; Lennox, Kimberly A; Bode, Nicole M.; Behlke, Mark A.; Möller, Thomas; Saxena, Smita; Moreno, Cristiane Araújo Martins; Costaguta, Giancarlo; Eijk, Kristel R. van; Phatnani, Hemali; Al‐Chalabi, Ammar; Başak, A. Nazlı; Berg, Leonard H van den; Hardiman, Orla; Landers, John E.; Mora, Jesús; Morrison, Karen E.; Shaw, Pamela J.; Veldink, Jan H.; Pfaff, Samuel L.; Yizhar, Ofer; Groß, Christina; Brown, Robert H.; Ravits, John; Harms, Matthew B.; Miller, Timothy M.; Hornstein, Eran

doi:10.1126/scitranslmed.aav5264

Cited by 44 publications

(55 citation statements)

References 71 publications

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“…Mir-218-5p is a microRNA found to be expressed in 20 vertebrate species (http://www.mirbase.org/). It has been implicated in tumorigenesis and cancer progression of different tumor entities (reviewed in [50]), as well as its role in the motor neuron development has recently been discovered [51,52]. However, regarding the role of miR-218 in chondrogenesis, the published literature is very limited and so far presents somewhat contradicting claims.…”

Section: Discussionmentioning

confidence: 99%

MiR-218 affects hypertrophic differentiation of human mesenchymal stromal cells during chondrogenesis via targeting RUNX2, MEF2C, and COL10A1

et al. 2020

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Background Human mesenchymal stromal cells (MSC) hold hopes for cartilage regenerative therapy due to their chondrogenic differentiation potential. However, undesirable occurrence of calcification after ectopic transplantation, known as hypertrophic degeneration, remains the major obstacle limiting application of MSC in cartilage tissue regeneration approaches. There is growing evidence that microRNAs (miRs) play essential roles in post-transcriptional regulation of hypertrophic differentiation during chondrogenesis. Aim of the study was to identify new miR candidates involved in repression of hypertrophy-related targets. Methods The miR expression profile in human articular chondrocytes (AC) was compared to that in hypertrophic chondrocytes derived from human MSC by microarray analysis, and miR expression was validated by qPCR. Putative targets were searched by in silico analysis and validated by miR reporter assay in HEK293T, by functional assays (western blotting and ALP-activity) in transiently transfected SaOS-2 cells, and by a miR pulldown assay in human MSC. The expression profile of miR-218 was assessed by qPCR during in vitro chondrogenesis of MSC and re-differentiation of AC. MSC were transfected with miR-218 mimic, and differentiation outcome was assessed over 28 days. MiR-218 expression was quantified in healthy and osteoarthritic cartilage of patients. Results Within the top 15 miRs differentially expressed between chondral AC versus endochondral MSC differentiation, miR-218 was selected as a candidate miR predicted to target hypertrophy-related genes. MiR-218 was downregulated during chondrogenesis of MSC and showed a negative correlation to hypertrophic markers, such as COL10A1 and MEF2C. It was confirmed in SaOS-2 cells that miR-218 directly targets hypertrophy-related COL10A1, MEF2C, and RUNX2, as a gain of ectopic miR-218 mimic caused drop in MEF2C and RUNX2 protein accumulation, with attenuation of COL10A1 expression and significant concomitant reduction of ALP activity. A miR pulldown assay confirmed that miR-218 directly targets RUNX2, MEF2C in human MSC. Additionally, the gain of miR-218 in human MSC attenuated hypertrophic markers (MEF2C, RUNX2, COL10A1, ALPL), although with no boost of chondrogenic markers (GAG deposition, COL2A1) due to activation of WNT/β-catenin signaling. Moreover, no correlation between miR-218 expression and a pathologic phenotype in the cartilage of osteoarthritis (OA) patients was found. Conclusions Although miR-218 was shown to target pro-hypertrophic markers MEF2C, COL10A1, and RUNX2 in human MSC during chondrogenic differentiation, overall, it could not significantly reduce the hypertrophic phenotype or boost chondrogenesis. This could be explained by a concomitant activation of WNT/β-catenin signaling counteracting the anti-hypertrophic effects of miR-218. Therefore, to achieve a full inhibition of the endochondral pathway, a whole class of anti-hypertrophic miRs, including miR-218, needs to be taken into consideration.

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Section: Discussionmentioning

confidence: 99%

MiR-218 affects hypertrophic differentiation of human mesenchymal stromal cells during chondrogenesis via targeting RUNX2, MEF2C, and COL10A1

et al. 2020

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“…In this study the authors identified the potassium channel KV10.1 as a novel miR-218 target that regulates neuronal activity. From sequencing thousands of ALS genomes, they also identified six rare miR-218-2 gene variants that failed to regulate neuronal activity due to reduced processing by DICER, further highlighting the importance of miR-218 in MNs ( Reichenstein et al, 2019 ).…”

Section: Neuronal Subtype Determination and Functionmentioning

confidence: 99%

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

Zolboot

Zampa

et al. 2021

Front. Mol. Neurosci.

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Characterizing the diverse cell types that make up the nervous system is essential for understanding how the nervous system is structured and ultimately how it functions. The astonishing range of cellular diversity found in the nervous system emerges from a small pool of neural progenitor cells. These progenitors and their neuronal progeny proceed through sequential gene expression programs to produce different cell lineages and acquire distinct cell fates. These gene expression programs must be tightly regulated in order for the cells to achieve and maintain the proper differentiated state, remain functional throughout life, and avoid cell death. Disruption of developmental programs is associated with a wide range of abnormalities in brain structure and function, further indicating that elucidating their contribution to cellular diversity will be key to understanding brain health. A growing body of evidence suggests that tight regulation of developmental genes requires post-transcriptional regulation of the transcriptome by microRNAs (miRNAs). miRNAs are small non-coding RNAs that function by binding to mRNA targets containing complementary sequences and repressing their translation into protein, thereby providing a layer of precise spatial and temporal control over gene expression. Moreover, the expression profiles and targets of miRNAs show great specificity for distinct cell types, brain regions and developmental stages, suggesting that they are an important parameter of cell type identity. Here, we provide an overview of miRNAs that are critically involved in establishing neural cell identities, focusing on how miRNA-mediated regulation of gene expression modulates neural progenitor expansion, cell fate determination, cell migration, neuronal and glial subtype specification, and finally cell maintenance and survival.

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“…To elucidate the tissue source of miR-181 we revisited previously reported Nanostring data 25 . miR-181a-5p is the ninth most abundant miRNA in laser capture micro-dissected human motor neurons of ALS patients and is also fairly abundant in the CNS in general 26 .…”

Section: Resultsmentioning

confidence: 99%

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

Magen

Coenen-Stass

Großkreutz

et al. 2019

Preprint

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word count: 203 Main text word count: 2738 words (excluding references and figure legends).No. of items (figures, tables): 4, 1 One Sentence Summary: higher plasma miR-181a-5p levels increase mortality risk in ALS patients. Abstract (210 words)Amyotrophic lateral sclerosis (ALS) is a ruthless neurodegenerative disease affecting the motor neuron system. Variability of disease progression has limited the effectiveness of ALS clinical trials, making novel tools for patient stratification at trial recruitment. Thus, better outcome measures are desperately needed in order to achieve therapeutic progress. Here, we investigate the potential of plasma cell-free microRNAs as biomarkers to predict ALS progression. We apply an unbiased high-throughput approach to define miRNA levels in a large cohort of ALS patients and controls. Crucially, we conduct our analysis also on longitudinal samples reflecting disease progression, and are able to integrate detailed clinical phenotyping in our analysis. We identify miR-181a-5p levels to be stable during disease course and demonstrate that high miR-181a-5p plasma levels predict shortened survival in ALS patients, with a 2.5 fold reduction in median survival for patients with high miR-181a-5p plasma levels. We replicated this finding in an independent validation cohort, where an eight-fold (×8) difference in miR-181a-5p levels between the two prognosis subgroups was robustly measurable by quantitative real time PCR. In conclusion, miR-181a-5p plasma levels can predict disease course in ALS suggesting it as a novel biomarker for patient stratification that might will greatly enhance the effectiveness of clinical trials.

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Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Cited by 44 publications

References 71 publications

MiR-218 affects hypertrophic differentiation of human mesenchymal stromal cells during chondrogenesis via targeting RUNX2, MEF2C, and COL10A1

MiR-218 affects hypertrophic differentiation of human mesenchymal stromal cells during chondrogenesis via targeting RUNX2, MEF2C, and COL10A1

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

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

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