Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of target transcripts. Prion diseases comprise a singular group of neurodegenerative conditions caused by endogenous, misfolded pathogenic (prion) proteins, associated with molecular aggregates. In humans, classical prion diseases include Creutzfeldt–Jakob disease, fatal familial insomnia, Gerstmann–Sträussler–Scheinker syndrome, and kuru. The aim of this review is to present the connections between miRNAs and prions, exploring how the interaction of both molecular actors may help understand the susceptibility, onset, progression, and pathological findings typical of such disorders, as well as the interface with some prion-like disorders, such as Alzheimer’s. Additionally, due to the inter-regulation of prions and miRNAs in health and disease, potential biomarkers for non-invasive miRNA-based diagnostics, as well as possible miRNA-based therapies to restore the levels of deregulated miRNAs on prion diseases, are also discussed. Since a cure or effective treatment for prion disorders still pose challenges, miRNA-based therapies emerge as an interesting alternative strategy to tackle such defying medical conditions.
Highlights
The natively folded version of the prion protein, named cellular prion (PrPC), is a cell-surface glycoprotein encoded by the endogenous mammalian gene Prnp, which is present in all vertebrates [4] and highly expressed in the brain, and at lower levels in most other tissues
These proteins present two structural conformations, the first acting as a template to the second, which is aggregation-prone, pathogenic and able to amplify its structural conformation. Many of these mammalian proteins are associated with neurodegenerative disorders, such as amyloid precursor protein in Alzheimer’s disease (AD), ataxin in amyotrophic lateral sclerosis (ALS), huntingtin in Huntington’s disease (HD) and a-synuclein in Parkinson’s disease (PD)
Interplay between miRNAs and Cellular Prions in Health. Since both prion protein and microRNAs are encoded by the mammalian genome, both of them are subjected to many levels of expression control, as well as inter-regulation
Summary
Prion (pronounced pree-on) is an atypical etiological agent composed solely of a misfolded protein—(proteinaceous infectious particle [1]), which affects mammals causing a group of slow, progressive, neurodegenerative, lethal, untreatable disorders known as transmissible spongiform encephalopathies (TSEs). In the last decade, a series of discoveries have evidenced that the ‘prion principle’ may not be limited to the prion protein itself, but rather to many other mammalian (for example, a-synuclein and ataxin) and fungal (Sup, Ure; reviewed in [11]) polypeptides which are able to have a prion-like behavior (“prionoids”; [6]). These proteins present two structural conformations, the first acting as a template to the second, which is aggregation-prone, pathogenic and able to amplify its structural conformation. Many of these mammalian proteins are associated with neurodegenerative disorders, such as amyloid precursor protein in Alzheimer’s disease (AD), ataxin in amyotrophic lateral sclerosis (ALS), huntingtin in Huntington’s disease (HD) and a-synuclein in Parkinson’s disease (PD) (reviewed in [12])
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