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Variability in Cerebrospinal Fluid MicroRNAs Through Life

Abstract

The development of the human brain starts in the first weeks of embryo differentiation. However, there are many relevant neurodevelopmental processes that take place after birth and during lifespan. Such a fine and changing scenario requires the coordinated expression of thousands of genes to achieve the proper specialization and inter-connectivity. In this context, microRNAs (miRNAs), which can modulate mRNA stability and translation, are gaining recognition for their involvement in both brain development and neurodevelopmental disorders. Therefore, cerebrospinal fluid (CSF) miRNAs should be perfectly differentiated in relevant age periods. In this study, we aimed to highlight the biological variability of miRNA expression in the CSF throughout life, which is also crucial for biomarker discovery in CNS pathologies, especially in children, where they are desperately needed. We analyzed the CSF microRNAome of 14 healthy children (aged 0–7.4 years) by smallRNA-Seq and compared it with previously published data in adults (N = 7) and elders (N = 11). miR-423-5p and miR-22-3p were overexpressed in the < 1 and > 3 years groups, respectively. Additionally, we detected 18 miRNAs that reached their highest peak of expression at different time-points during the lifespan and sets of miRNAs that were exclusively expressed in a specific age group. On the contrary, miR-191-5p showed stable expression in CSF from the first year of life. Our results remark the complex differential miRNA expression profile that can be observed through life, which underlines the need for including appropriate age-matched controls when the expression of CSF miRNAs is analyzed in different pathological contexts.

Graphical abstract

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Abbreviations

<1:

Less than 1 year group

1-2:

From 1 to 2 years group

>3:

More than 3 years group

ADU:

Adult group

CHI:

Children (individuals from 0 to 7.4 years old)

CSF:

Cerebrospinal fluid

CPDB:

ConsensusPathDB web tool

ELD:

Elderly group

EVs:

Extracellular vesicles

KEGG:

Kyoto Encyclopedia of Genes and Genomes

mRNA:

Messenger RNA

miRNA:

MicroRNA

RT-qPCR:

Quantitative PCR

SmallRNAseq:

Small RNA sequencing

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Acknowledgments

We extend special thanks to the Department of Pediatric Emergency team at Cruces University Hospital for their collaboration in obtaining clinical samples: Yordana Acedo, Pilar Alonso, Beatriz Azkunaga, Yolanda Ballestero, Elena Daghoum, Ana Fernandez, Iker Gangoiti, Silvia Garcia, Borja Gomez, María Gonzalez, Edurne Lopez, Roser Martinez, Santiago Mintegi, Ohiane Morientes, Mikel Olabarri, Natalia Paniagua, and María Angeles Ruiz.

Funding

This work was supported by the Basque Government (IT989-16), the Spanish Ministry of Economy and Competitiveness MINECO (SAF2015-66312), and the Ramon Areces Foundation (FRA-17-JMF). We thank MINECO for the TenTaCles (Spanish Excellence Network in Exosomes) and the Severo Ochoa Excellence Accreditation (SEV-2016-0644).

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Correspondence to Endika Prieto-Fernández, Elixabet Lopez-Lopez or Idoia Martin-Guerrero.

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Prieto-Fernández, E., Lopez-Lopez, E., Martin-Guerrero, I. et al. Variability in Cerebrospinal Fluid MicroRNAs Through Life. Mol Neurobiol 57, 4134–4142 (2020). https://doi.org/10.1007/s12035-020-02011-3

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Keywords

  • Cerebrospinal fluid
  • MicroRNAs
  • Children
  • Biomarkers
  • Biological variability