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

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.

MicroRNA Alterations in the Brain and Body Fluids of Humans and Animal Prion Disease Models: Current Status and Perspectives

“…Studies on miRNA alterations were conducted in the brain of patients afflicted with sporadic Creutzfeldt-Jakob disease (sCJD) ( Montag et al, 2009 ; Lukiw et al, 2011 ; Llorens et al, 2018 ), Fatal Familial Insomnia (FFI) ( Llorens et al, 2018 ) and Gerstmann–Sträussler–Scheinker syndrome (GSS) ( Lukiw et al, 2011 ).…”

Genome‐wide identification of microRNAs regulating the human prion protein

“…In prion disease specifically, miR‐124‐3p has been shown to become significantly upregulated in mouse hippocampal CA1 neurons at 70 and 90 days post scrapie infection, while contrarily becoming downregulated at 130 and 160 days post infection . In human post‐mortem sCJD frontal cortical and cerebellar samples, miR‐124‐3p was similarly found to be decreased relative to control tissues . This conserved temporal regulation in miR‐124‐3p expression indicates a potential role of this miRNA in prion disease pathology.…”

“…Several miRNAs, most notably miR‐124‐3p, miR‐146a‐5p and miR‐342‐3p, have been found to become consistently deregulated following prion infection in GT1‐7 neuronal cells , RML inoculation in mice , scrapie infection in sheep , BSE infection in macaques and sporadic Creutzfeldt‐Jakob disease (sCJD) in humans . These miRNAs also display similar spatiotemporal expression patterns during prion disease pathogenesis and in sCJD subtypes , implying that mechanisms of deregulation may be conserved across species. Intriguingly, miR‐124‐3p, which is highly expressed in almost all brain regions , has also been found to be downregulated in the brains of patients suffering from Alzheimer’s and Huntington’s disease .…”

Regulation of MicroRNAs-Mediated Autophagic Flux: A New Regulatory Avenue for Neurodegenerative Diseases With Focus on Prion Diseases

“…In CB, miRNAs 146a-5p, 154-5p, 26a-5p, 378a-3p, 449a, 142-3p, let7i-3p, and 5701 were upregulated, and miRNAs 124-3p and 877-5p were downregulated in sCJD. The rest of miRNAs, which expression was only altered in FC did not present changes in the CB ( Llorens et al, 2018 ).…”

“…Similarly, Miller et al (2013) also showed the upregulation of miRNA-16 in PD patients. Llorens et al (2018) demonstrated the miRNA signature in frontal cortex (FC) and cerebellum (CB) of sporadic CJD patients. In sCJD FC, miRNAs 29b-3p, 342-3p, 146a-5p, 154-5p, 195-5p, 26a-5p, 16-5p, 449a, 142-3p, let7i-5p, and 135a-5p were upregulated, while miRNAs 124-3p, 331-3p, 877-5p, and 125a-5p were downregulated compared to controls.…”