TY  - JOUR
AU  - Llorens, Franc
AU  - Thüne, Katrin
AU  - Martí, Eulàlia
AU  - Kanata, Eirini
AU  - Dafou, Dimitra
AU  - Díaz-Lucena, Daniela
AU  - Vivancos, Ana
AU  - Shomroni, Orr
AU  - Zafar, Saima
AU  - Schmitz, Matthias
AU  - Michel, Uwe
AU  - Fernández-Borges, Natalia
AU  - Andréoletti, Olivier
AU  - Del Río, José Antonio
AU  - Díez, Juana
AU  - Fischer, Andre
AU  - Bonn, Stefan
AU  - Sklaviadis, Theodoros
AU  - Torres, Juan Maria
AU  - Ferrer, Isidre
AU  - Zerr, Inga
TI  - Regional and subtype-dependent miRNA signatures in sporadic Creutzfeldt-Jakob disease are accompanied by alterations in miRNA silencing machinery and biogenesis.
JO  - PLoS pathogens
VL  - 14
IS  - 1
SN  - 1553-7374
CY  - Lawrence, Kan.
PB  - PLoS
M1  - DZNE-2020-06092
SP  - e1006802
PY  - 2018
AB  - 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.
KW  - Adult
KW  - Aged
KW  - Aged, 80 and over
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Case-Control Studies
KW  - Creutzfeldt-Jakob Syndrome: classification
KW  - Creutzfeldt-Jakob Syndrome: genetics
KW  - Creutzfeldt-Jakob Syndrome: pathology
KW  - Female
KW  - Gene Expression Profiling
KW  - Humans
KW  - Male
KW  - MicroRNAs: biosynthesis
KW  - MicroRNAs: genetics
KW  - Middle Aged
KW  - RNA Interference
KW  - Transcriptome
KW  - MicroRNAs (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29357384
C2  - pmc:PMC5794191
DO  - DOI:10.1371/journal.ppat.1006802
UR  - https://pub.dzne.de/record/139770
ER  -