Regional and subtype-dependent miRNA signatures in sporadic Creutzfeldt-Jakob disease are accompanied by alterations in miRNA silencing machinery and biogenesis

PLoS Pathog. 2018 Jan 22;14(1):e1006802. doi: 10.1371/journal.ppat.1006802. eCollection 2018 Jan.

Abstract

Increasing evidence indicates that microRNAs (miRNAs) are contributing factors to neurodegeneration. Alterations in miRNA signatures have been reported in several neurodegenerative dementias, but data in prion diseases are restricted to ex vivo and animal models. The present study identified significant miRNA expression pattern alterations in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) patients. These changes display a highly regional and disease subtype-dependent regulation that correlates with brain pathology. We demonstrate that selected miRNAs are enriched in sCJD isolated Argonaute(Ago)-binding complexes in disease, indicating their incorporation into RNA-induced silencing complexes, and further suggesting their contribution to disease-associated gene expression changes. Alterations in the miRNA-mRNA regulatory machinery and perturbed levels of miRNA biogenesis key components in sCJD brain samples reported here further implicate miRNAs in sCJD gene expression (de)regulation. We also show that a subset of sCJD-altered miRNAs are commonly changed in Alzheimer's disease, dementia with Lewy bodies and fatal familial insomnia, suggesting potential common mechanisms underlying these neurodegenerative processes. Additionally, we report no correlation between brain and cerebrospinal fluid (CSF) miRNA-profiles in sCJD, indicating that CSF-miRNA profiles do not faithfully mirror miRNA alterations detected in brain tissue of human prion diseases. Finally, utilizing a sCJD MM1 mouse model, we analyzed the miRNA deregulation patterns observed in sCJD in a temporal manner. While fourteen sCJD-related miRNAs were validated at clinical stages, only two of those were changed at early symptomatic phase, suggesting that the miRNAs altered in sCJD may contribute to later pathogenic processes. Altogether, the present work identifies alterations in the miRNA network, biogenesis and miRNA-mRNA silencing machinery in sCJD, whereby contributions to disease mechanisms deserve further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Brain / metabolism
  • Brain / pathology
  • Case-Control Studies
  • Creutzfeldt-Jakob Syndrome / classification*
  • Creutzfeldt-Jakob Syndrome / genetics*
  • Creutzfeldt-Jakob Syndrome / pathology
  • Female
  • Gene Expression Profiling
  • Humans
  • Male
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Middle Aged
  • RNA Interference*
  • Transcriptome*

Substances

  • MicroRNAs

Supplementary concepts

  • Creutzfeldt-Jakob Disease, Sporadic

Grant support

This work was supported by the Robert Koch Institute through funds from the Federal Ministry of Health (grant no. 1369-341) to IZ, by the Seventh Framework Program of the European Commission (Grant No. 278486 [DEVELAGE project]), by the Spanish Ministry of Health, Instituto Carlos III (Fondo de Investigación Sanitaria [FIS] PI1100968, FIS PI14/00757 and by CIBERNED (Network center for biomedical research of neurodegenerative diseases) project BESAD-P to IF, by the Spanish Ministry of Health, Instituto Carlos III-Fondo Social Europeo (CP16/00041) to FL, by the Red Nacional de priones (AGL2015-71764-REDT- MINECO) to JADR, FL, IZ, JMT and IF, by the bilateral IKYDA project (ID 57260006) to FL, IZ and TS, by the Spanish Ministry of Economy and Competitiveness (BFU2016-80039-R) (AEI/MINEICO/FEDER, UE) and the “Maria de Maeztu” Program for Units of Excellence in R&D (MDM-2014-0370) to JD, by the Spanish Ministry of Economy and Competitiveness (SAF2014-60551-R) to EM and by the Spanish Ministry of Economy, Industry and Competitiveness (MEICO) (BFU2015-67777-R), the Generalitat de Catalunya (SGR2014-1218), CIBERNED (PRY-2016-2, MFDEND), La Caixa Obra Social Foundation and La Marató de TV3 to JADR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.