Molecular pathogenesis of prion diseases

Introduction: Prion diseases or transmissible spongiform encephalopathies (TSEs) are rare, fatal and incurable neurodegenerative disorders of humans and animals (Prusiner, 1998). In humans, prion diseases occur with unique aetiology as sporadic, genetic or infectious disorders. Sporadic cases of prion diseases, which account for the majority of casualties (up to 85% of all cases), are of unknown origin; the genetic forms are less frequent (up to 15%), while the infectious cases are extremely rare with an incidence of less than 1% (Prusiner, 2001). Creutzfeldt-Jakob disease (CJD), Gerstmann-Str\ue4ussler-Scheinker (GSS) syndrome, Fatal Familial Insomnia (FFI) are examples of human prion diseases. In animals the disease is mostly infectious and the mode of transmission is horizontal. Prion diseases include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease of deer, elk, and moose (Williams, 2005). The agents responsible for prion diseases are infectious proteins named prions. The term \u2018prion\u2019 was coined when Stanley B. Prusiner introduced the concept of proteinaceous infectious particles (Prusiner, 1982). Since the introduction of this once heretical notion, mounting evidence has strengthened its validity. In the next sections of this chapter we present and discuss the peculiar complexity of the molecular pathogenesis of prion diseases in humans and animals

De novo prions

Prions are responsible for a heterogeneous group of fatal neurodegenerative diseases. They occur in three forms - sporadic, genetic, or acquired - and involve non-covalent post-translational modifications of the cellular prion protein (PrP(C)). Prions (PrP(Sc)) are characterized by their infectious properties and intrinsic ability to act as a template, converting the normal, physiological PrP(C) into the pathological form, PrP(Sc). The 'protein-only' hypothesis, postulated by Stanley B Prusiner, implies that the generation of de novo prions is possible. Exciting recent work, in vivo and in vitro, has further strengthened this postulate

PRND (Prion Protein 2 (Dublet))

Review on PRND, with data on DNA/RNA, on the protein encoded and where the gene is implicated

Small-Molecule Theranostic Probes: A Promising Future in Neurodegenerative Diseases

Prion diseases are fatal neurodegenerative illnesses, which include Creutzfeldt-Jakob disease in humans and scrapie, chronic wasting disease, and bovine spongiform encephalopathy in animals. They are caused by unconventional infectious agents consisting primarily of misfolded, aggregated, \u3b2 -sheet-rich isoforms, denoted prions, of the physiological cellular prion protein (PrP(C)). Many lines of evidence suggest that prions (PrP(Sc)) act both as a template for this conversion and as a neurotoxic agent causing neuronal dysfunction and cell death. As such, PrP(Sc) may be considered as both a neuropathological hallmark of the disease and a therapeutic target. Several diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, and prion disease). Examples of these probes are Congo red, thioflavin T, and their derivatives. We synthesized a series of styryl derivatives, denoted theranostics, and studied their therapeutic and/or diagnostic potentials. Here we review the salient traits of these small molecules that are able to detect and modulate aggregated forms of several proteins involved in protein misfolding diseases. We then highlight the importance of further studies for their practical implications in therapy and diagnostics

Chronic \u3b1-synuclein accumulation in rat hippocampus induces lewy bodies formation and specific cognitive impairments

Occurrence of Lewy bodies (LBs)/Lewy neurites (LNs) containing misfolded fibrillar a-synuclein (a-syn) is one of the pathologic hallmarks of memory impairment-linked synucleinopathies, such as Parkinson\u2019s disease (PD) and dementia with LBs (DLB). While it has been shown that brainstem LBs may contribute to motor symptoms, the neuropatho-logical substrates for cognitive symptoms are still elusive. Here, recombinant mouse a-syn fibrils were bilaterally injected in the hippocampus of female Sprague Dawley rats, which underwent behavioral testing for sensorimotor and spatial learning and memory abilities. No sensorimotor deficits affecting Morris water maze task performance were observed, nor was any reference memory disturbances detectable in injected animals. By contrast, significant impairments in working memory performance became evident at 12 months postinjection. These deficits were associated to a time-dependent increase in the levels of phosphorylated a-syn at Ser129 and in the stereologically esti-mated numbers of proteinase K (PK)-resistant a-syn aggregates within the hippocampus. Interestingly, pathologic a-syn aggregates were found in the entorhinal cortex and, by 12 months postinjection, also in the vertical limb of the diagonal band and the piriform cortices. No pathologic a-syn deposits were found within the substantia nigra (SN), the ventral tegmental area (VTA), or the striatum, nor was any loss of dopaminergic, noradrenergic, or cholinergic neurons detected in a-syn-injected animals, compared with controls. This would suggest that the behavioral impairmentsseeninthea-syn-injected animals might be determined by the long-term a-syn neuropathology, rather than by neurodegeneration per se, thus leading to the onset of working memory deficits

Soil humic substances hinder the propagation of prions

Prions are infectious pathogens causing fatal neurodegenerative disorders, known as transmissible spongiform encephalopathies (TSEs), or prion diseases, which affect different mammalian species. TSEs include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in mule deer, elk, and moose (cervids), and Creutzfeldt-Jakob disease (CJD) in humans. The prominent, if not only, component of prions is a misfolded conformer (PrPSc) of a constitutive sialoglycoprotein, the cellular prion protein (PrPC). A notable feature of prion diseases is horizontal transmission between grazing animals, implying that contaminated soil may serve to propagate the disease. In this respect, it has been reported that grazing animals ingest from tens to hundreds grams of soil per day, either incidentally through the diet, or deliberately in answering salt needs, and that mule deer can develop CWD after grazing in locations that previously housed infected \u202

Prion and prion-like protein strains: Deciphering the molecular basis of heterogeneity in neurodegeneration

Increasing evidence suggests that neurodegenerative disorders share a common pathogenic feature: The presence of deposits of misfolded proteins with altered physicochemical properties in the Central Nervous System. Despite a lack of infectivity, experimental data show that the replication and propagation of neurodegenerative disease-related proteins including amyloid-\u3b2 (A\u3b2), tau, \u3b1-synuclein and the transactive response DNA-binding protein of 43 kDa (TDP-43) share a similar pathological mechanism with prions. These observations have led to the terminology of "prion-like" to distinguish between conditions with noninfectious characteristics but similarities with the prion replication and propagation process. Prions are considered to adapt their conformation to changes in the context of the environment of replication. This process is known as either prion selection or adaptation, where a distinct conformer present in the initial prion population with higher propensity to propagate in the new environment is able to prevail over the others during the replication process. In the last years, many studies have shown that prion-like proteins share not only the prion replication paradigm but also the specific ability to aggregate in different conformations, i.e., strains, with relevant clinical, diagnostic and therapeutic implications. This review focuses on the molecular basis of the strain phenomenon in prion and prion-like proteins

Unique Structural Features of Mule Deer Prion Protein Provide Insights into Chronic Wasting Disease

Chronic wasting disease (CWD) is a highly infectious prion disease of cervids. Accumulation of prions, the disease-specific structural conformers of the cellular prion protein (PrPC), in the central nervous system, is the key pathological event of the disorder. The analysis of cervid PrPC sequences revealed the existence of polymorphism at position 226, in which deer PrP contains glutamine (Q), whereas elk PrP contains glutamate (E). The effects of this polymorphism on CWD are still unknown. We determined the high-resolution nuclear magnetic resonance structure of the mule deer prion protein that was compared to previously published PrP structures of elk and white-tailed deer. We found that the polymorphism Q226E could influence the long-range intramolecular interactions and packing of the \u3b22-\u3b12 loop and the C-terminus of the \u3b13 helix of cervid PrP structures. This solvent-accessible epitope is believed to be involved in prion conversion. Additional differences were observed at the beginning of the well-defined C-terminus domain, in the \u3b12-\u3b13 region, and in its interactions with the \u3b11 helix. Here, we highlight the importance of the PrP structure in prion susceptibility and how single amino acid differences might influence the overall protein folding

Evidence of Orientation-Dependent Early States of Prion Protein Misfolded Structures from Single Molecule Force Spectroscopy

Prion diseases are neurodegenerative disorders characterized by the presence of oligomers and amyloid fibrils. These are the result of protein aggregation processes of the cellular prion protein (PrPC) into amyloidal forms denoted as prions or PrPSc. We employed atomic force microscopy (AFM) for single molecule pulling (single molecule force spectroscopy, SMFS) experiments on the recombinant truncated murine prion protein (PrP) domain to characterize its conformations and potential initial oligomerization processes. Our AFM-SMFS results point to a complex scenario of structural heterogeneity of PrP at the monomeric and dimer level, like other amyloid proteins involved in similar pathologies. By applying this technique, we revealed that the PrP C-terminal domain unfolds in a two-state process. We used two dimeric constructs with different PrP reciprocal orientations: one construct with two sequential PrP in the N- to C-terminal orientation (N-C dimer) and a second one in the C- to C-terminal orientation (C-C dimer). The analysis revealed that the different behavior in terms of unfolding force, whereby the dimer placed C-C dimer unfolds at a higher force compared to the N-C orientation. We propose that the C-C dimer orientation may represent a building block of amyloid fibril formation