Abstract
Prion diseases are transmissible progressive neurodegenerative conditions characterized by rapid neuronal loss accompanied by a heterogeneous neuropathology, including spongiform degeneration, gliosis and protein aggregation. The pathogenic mechanisms and the origins of prion diseases remain unclear on the molecular level. Even though neurodegenerative diseases, including prion diseases, represent distinct entities, their pathogenesis shares a number of features including disturbed protein homeostasis, an overload of protein clearance pathways, the aggregation of pathological altered proteins, and the dysfunction and/or loss of specific neuronal populations. Recently, direct links have been established between neurodegenerative diseases and miRNA dysregulated patterns. miRNAs are a class of small non-coding RNAs involved in the fundamental post-transcriptional regulation of gene expression. Studies of miRNA alterations in the brain and body fluids in human prion diseases provide important insights into potential miRNA-associated disease mechanisms and biomarker candidates. miRNA alterations in prion disease models represent a unique tool to investigate the cause-consequence relationships of miRNA dysregulation in prion disease pathology, and to evaluate the use of miRNAs in diagnosis as biomarkers. Here, we provide an overview of studies on miRNA alterations in human prion diseases and relevant disease models, in relation to pertinent studies on other neurodegenerative diseases.
Highlights
Prion diseases are rapidly progressive, fatal neurodegenerative disorders, characterized by widespread neuronal loss, gliosis, spongiform change and deposition of the pathological PrPSc protein in the Central Nervous System (CNS) (Appleby et al, 2009)
They are involved in several biological processes, including neuronal function and survival (Zhang et al, 2007). miRNA biogenesis includes several processing steps mediated by multiple miRNA maturating proteins in the nucleus and cytoplasm (Ha and Kim, 2014). miRNAs are usually transcribed by RNA polymerase II as long, primary miRNA transcripts and undergo a series of cleavage events by the ribonucleases Drosha and Dicer, as well as post-transcriptional modifications, such as splicing and editing (Slezak-Prochazka et al, 2010)
The upregulated in prion diseases miR-146a-5p has been found overexpressed in active Multiple Sclerosis (MS) lesions (Junker et al, 2009), and in Alzheimer’s disease (AD) brain (Sethi and Lukiw, 2009; Müller et al, 2014) associated with different cellular contexts, including neurons (Wang et al, 2016) and astrocytes (Cui et al, 2010; Arena et al, 2017)
Summary
Prion diseases are rapidly progressive, fatal neurodegenerative disorders, characterized by widespread neuronal loss, gliosis, spongiform change and deposition of the pathological PrPSc protein in the Central Nervous System (CNS) (Appleby et al, 2009). Increased levels of miR-16-5p, miR-29b-3p, let-7i-3p, miR-378a-3p, miR-449a, and miR-154-5p were observed in sCJD patients and in the sCJD mice model brain, suggesting disease-specific miRNA profiles (Llorens et al, 2018).
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