Abstract
Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative disorders that affect humans and other mammals. The etiologic agents common to these diseases are misfolded conformations of the prion protein (PrP). The molecular mechanisms that trigger the structural conversion of the normal cellular PrP (PrPC) into the pathogenic conformer (PrPSc) are still poorly understood. It is proposed that a molecular cofactor would act as a catalyst, lowering the activation energy of the conversion process, therefore favoring the transition of PrPC to PrPSc. Several in vitro studies have described physical interactions between PrP and different classes of molecules, which might play a role in either PrP physiology or pathology. Among these molecules, nucleic acids (NAs) are highlighted as potential PrP molecular partners. In this context, the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) methodology has proven extremely valuable to investigate PrP–NA interactions, due to its ability to select small nucleic acids, also termed aptamers, that bind PrP with high affinity and specificity. Aptamers are single-stranded DNA or RNA oligonucleotides that can be folded into a wide range of structures (from harpins to G-quadruplexes). They are selected from a nucleic acid pool containing a large number (1014–1016) of random sequences of the same size (~20–100 bases). Aptamers stand out because of their potential ability to bind with different affinities to distinct conformations of the same protein target. Therefore, the identification of high-affinity and selective PrP ligands may aid the development of new therapies and diagnostic tools for TSEs. This review will focus on the selection of aptamers targeted against either full-length or truncated forms of PrP, discussing the implications that result from interactions of PrP with NAs, and their potential advances in the studies of prions. We will also provide a critical evaluation, assuming the advantages and drawbacks of the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) technique in the general field of amyloidogenic proteins.
Highlights
Aberrant prion proteins (PrPs) responsible for the transmissible spongiform encephalopathies (TSEs) are misfolded conformations of the natively expressed prion protein, the innocuous cellular PrP (PrPC) [1]
The results showed that the high affinity for bovine PrP (bPrP)-β by the selected aptamer is abolished at a high salt concentration (1M NaCl); this behavior is not observed for the native bPrP, which maintains approximately the same interaction affinity for the same selected aptamer in equal experimental conditions [71]
Protein interactions with nucleic acids (NAs) are governed by several molecular forces, including hydrogen bonding mediated by aqueous solvent, electrostatic, hydrophobic, and stacking interactions [52]
Summary
Aberrant prion proteins (PrPs) responsible for the transmissible spongiform encephalopathies (TSEs) are misfolded conformations of the natively expressed prion protein, the innocuous cellular PrP (PrPC) [1]. High-resolution studies have revealed two structurally distinct domains: the flexible N-terminal region (residues 23–~120) and the globular C-terminal domain (residues ~120–231), the latter composed of three α-helices and a small antiparallel β-sheet [4,5] Is it still not known how the drastic conformational changes occur in the PrPC structure—even without any mutations in the PRNP gene—to give rise to the abnormal PrPSc. once formed, PrPSc can propagate in an autocatalytic manner, recruiting more PrPC to fold into new PrPSc, leading to its accumulation in tissues with severe cellular damage and further neurodegeneration [6]. It postulates that the presence of an adjuvant factor that interacts with PrP favors its interconversion, aggregation, and infectivity [13,16,18,19,20] Such a cofactor may act as a catalyst in PrP conversion, lowering the high-energy barrier that prevents the spontaneous conversion of PrPC into PrPSc (Figure 1).
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