-
The Journal of Biological Chemistry Nov 2023Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant...
Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant cellular prion protein (PrP) to β-sheet-rich pathological aggregated form of PrP in many mammalian species. Dogs exhibit resistance to prion diseases, but the mechanism behind the phenomenon remains poorly understood. Compared with human PrP and mouse PrP, dog PrP has two unique amino acid residues, Arg177 and Asp159. Because PrP contains a low-complexity and intrinsically disordered region in its N-terminal domain, it undergoes liquid-liquid phase separation (LLPS) in vitro and forms protein condensates. However, little is known about whether these two unique residues modulate the formation of PrP condensates. Here, using confocal microscopy, fluorescence recovery after photobleaching assays, thioflavin T binding assays, and transmission electron microscopy, we report that Arg177 and Asp159 from the dog PrP slow the LLPS of full-length human PrP, shifting the equilibrium phase boundary to higher protein concentrations and inhibit amyloid formation of the human protein. In sharp contrast, His177 and Asn159 from the human PrP enhance the LLPS of full-length dog PrP, shifting the equilibrium phase boundary to lower protein concentrations, and promote fibril formation of the canid protein. Collectively, these results demonstrate how LLPS and amyloid formation of PrP are inhibited by a single residue Arg177 or Asp159 associated with prion disease resistance, and how LLPS and fibril formation of PrP are promoted by a single residue His177 or Asn159. Therefore, Arg177/His177 and Asp159/Asn159 are key residues in modulating PrP liquid-phase condensation.
Topics: Mice; Dogs; Humans; Animals; Prion Proteins; Prions; Amyloid; Amyloidogenic Proteins; Prion Diseases; Mammals
PubMed: 37805139
DOI: 10.1016/j.jbc.2023.105329 -
Nature Reviews. Disease Primers Feb 2024
Topics: Humans; Creutzfeldt-Jakob Syndrome; Prion Diseases; Brain
PubMed: 38424445
DOI: 10.1038/s41572-024-00506-0 -
Redox Biology Jun 2024Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are protein-based neurodegenerative disorders (NDs) affecting humans and animals. They...
Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are protein-based neurodegenerative disorders (NDs) affecting humans and animals. They are characterized by the conformational conversion of the normal cellular prion protein, PrP, into the pathogenic isoform, PrP. Prion diseases are invariably fatal and despite ongoing research, no effective prophylactic or therapeutic avenues are currently available. Anthocyanins (ACNs) are unique flavonoid compounds and interest in their use as potential neuroprotective and/or therapeutic agents against NDs, has increased significantly in recent years. Therefore, we investigated the potential anti-oxidant and anti-prion effects of Oenin and Myrtillin, two of the most common anthocyanins, using the most accepted in the field overexpressing PrPin vitro model and a cell free protein aggregation model. Our results, indicate both anthocyanins as strong anti-oxidant compounds, upregulating the expression of genes involved in the anti-oxidant response, and reducing the levels of Reactive Oxygen Species (ROS), produced due to pathogenic prion infection, through the activation of the Keap1-Nrf2 pathway. Importantly, they showcased remarkable anti-prion potential, as they not only caused the clearance of pathogenic PrP aggregates, but also completely inhibited the formation of PrP fibrils in the Cerebrospinal Fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD). Therefore, Oenin and Myrtillin possess pleiotropic effects, suggesting their potential use as promising preventive and/or therapeutic agents in prion diseases and possibly in the spectrum of neurodegenerative proteinopathies.
Topics: Anthocyanins; Humans; Reactive Oxygen Species; NF-E2-Related Factor 2; Antioxidants; Prion Diseases; Kelch-Like ECH-Associated Protein 1; Animals; PrPSc Proteins; Signal Transduction
PubMed: 38565068
DOI: 10.1016/j.redox.2024.103133 -
Life (Basel, Switzerland) Jul 2023Amyloids were conventionally referred to as extracellular and intracellular accumulation of Aβ42 peptide, which causes the formation of plaques and neurofibrillary... (Review)
Review
Amyloids were conventionally referred to as extracellular and intracellular accumulation of Aβ42 peptide, which causes the formation of plaques and neurofibrillary tangles inside the brain leading to the pathogenesis in Alzheimer's disease. Subsequently, amyloid-like deposition was found in the etiology of prion diseases, Parkinson's disease, type II diabetes, and cancer, which was attributed to the aggregation of prion protein, α-Synuclein, islet amyloid polypeptide protein, and p53 protein, respectively. Hence, traditionally amyloids were considered aggregates formed exclusively by proteins or peptides. However, since the last decade, it has been discovered that other metabolites, like single amino acids, nucleobases, lipids, glucose derivatives, etc., have a propensity to form amyloid-like toxic assemblies. Several studies suggest direct implications of these metabolite assemblies in the patho-physiology of various inborn errors of metabolisms like phenylketonuria, tyrosinemia, cystinuria, and Gaucher's disease, to name a few. In this review, we present a comprehensive literature overview that suggests amyloid-like structure formation as a common phenomenon for disease progression and pathogenesis in multiple syndromes. The review is devoted to providing readers with a broad knowledge of the structure, mode of formation, propagation, and transmission of different extracellular amyloids and their implications in the pathogenesis of diseases. We strongly believe a review on this topic is urgently required to create awareness about the understanding of the fundamental molecular mechanism behind the origin of diseases from an amyloid perspective and possibly look for a common therapeutic strategy for the treatment of these maladies by designing generic amyloid inhibitors.
PubMed: 37511898
DOI: 10.3390/life13071523 -
Pathogens (Basel, Switzerland) Feb 2024Chronic wasting disease (CWD) is a prion disease affecting cervid species, both free-ranging and captive populations. As the geographic range continues to expand and... (Review)
Review
Chronic wasting disease (CWD) is a prion disease affecting cervid species, both free-ranging and captive populations. As the geographic range continues to expand and disease prevalence continues to increase, CWD will have an impact on cervid populations, local economies, and ecosystem health. Mitigation of this "wicked" disease will require input from many different stakeholders including hunters, landowners, research biologists, wildlife managers, and others, working together. The NC1209 (North American interdisciplinary chronic wasting disease research consortium) is composed of scientists from different disciplines involved with investigating and managing CWD. Leveraging this broad breadth of expertise, the Consortium has created a state-of-the-science review of five key aspects of CWD, including current diagnostic capabilities for detecting prions, requirements for validating these diagnostics, the role of environmental transmission in CWD dynamics, and potential zoonotic risks associated with CWD. The goal of this review is to increase stakeholders', managers', and decision-makers' understanding of this disease informed by current scientific knowledge.
PubMed: 38392876
DOI: 10.3390/pathogens13020138 -
Progress in Molecular Biology and... 2024The scientific community is very interested in protein aggregation because of its involvement in several neurodegenerative diseases and its significance in industry.... (Review)
Review
The scientific community is very interested in protein aggregation because of its involvement in several neurodegenerative diseases and its significance in industry. Remarkably, fibrillar aggregates are utilized naturally for constructing structural scaffolds or creating biological switches and may be intentionally designed to construct versatile nanomaterials. Consequently, there is a significant need to rationalize and predict protein aggregation. Researchers have developed various computational methodologies and algorithms to predict protein aggregation and understand its underlying mechanics. This chapter aims to summarize the significant advancements in computational methods, accessible resources, and prospective developments in the field of in silico research. We assess the existing computational tools for predicting protein aggregation propensities, detecting areas that are prone to sequential and structural aggregation, analyzing the effects of mutations on protein aggregation, or identifying prion-like domains.
Topics: Protein Aggregates; Humans; Proteins; Computational Biology; Algorithms
PubMed: 38811082
DOI: 10.1016/bs.pmbts.2024.03.005 -
Cells Oct 2023Prion diseases are neurodegenerative disorders that are progressive, incurable, and deadly. The prion consists of PrP, the misfolded pathogenic isoform of the cellular... (Review)
Review
Prion diseases are neurodegenerative disorders that are progressive, incurable, and deadly. The prion consists of PrP, the misfolded pathogenic isoform of the cellular prion protein (PrP). PrP is involved in a variety of physiological functions, including cellular proliferation, adhesion, differentiation, and neural development. Prion protein is expressed on the membrane surface of a variety of stem cells (SCs), where it plays an important role in the pluripotency and self-renewal matrix, as well as in SC differentiation. SCs have been found to multiply the pathogenic form of the prion protein, implying their potential as an in vitro model for prion diseases. Furthermore, due to their capability to self-renew, differentiate, immunomodulate, and regenerate tissue, SCs are prospective cell treatments in many neurodegenerative conditions, including prion diseases. Regenerative medicine has become a new revolution in disease treatment in recent years, particularly with the introduction of SC therapy. Here, we review the data demonstrating prion diseases' biology and molecular mechanism. SC biology, therapeutic potential, and its role in understanding prion disease mechanisms are highlighted. Moreover, we summarize preclinical studies that use SCs in prion diseases.
Topics: Humans; Prion Proteins; Prion Diseases; Prions; Neurodegenerative Diseases; Stem Cells
PubMed: 37830627
DOI: 10.3390/cells12192413 -
The Journal of Biological Chemistry Jul 2023Fibrils of the microtubule-associated protein tau are intimately linked to the pathology of Alzheimer's disease (AD) and related neurodegenerative disorders. A current...
Fibrils of the microtubule-associated protein tau are intimately linked to the pathology of Alzheimer's disease (AD) and related neurodegenerative disorders. A current paradigm for pathology spreading in the human brain is that short tau fibrils transfer between neurons and then recruit naive tau monomers onto their tips, perpetuating the fibrillar conformation with high fidelity and speed. Although it is known that the propagation could be modulated in a cell-specific manner and thereby contribute to phenotypic diversity, there is still limited understanding of how select molecules are involved in this process. MAP2 is a neuronal protein that shares significant sequence homology with the repeat-bearing amyloid core region of tau. There is discrepancy about MAP2's involvement in pathology and its relationship with tau fibrillization. Here, we employed the entire repeat regions of 3R and 4R MAP2, to investigate their modulatory role in tau fibrillization. We find that both proteins block the spontaneous and seeded aggregation of 4R tau, with 4R MAP2 being slightly more potent. The inhibition of tau seeding is observed in vitro, in HEK293 cells, and in AD brain extracts, underscoring its broader scope. MAP2 monomers specifically bind to the end of tau fibrils, preventing recruitment of further tau and MAP2 monomers onto the fibril tip. The findings uncover a new function for MAP2 as a tau fibril cap that could play a significant role in modulating tau propagation in disease and may hold promise as a potential intrinsic protein inhibitor.
Topics: Humans; Alzheimer Disease; Amyloid; Cytoskeleton; HEK293 Cells; Microtubule-Associated Proteins; Neurons; tau Proteins
PubMed: 37286038
DOI: 10.1016/j.jbc.2023.104891 -
IScience Dec 2023Prions cause fatal neurodegenerative diseases and exhibit remarkable durability, which engenders a wide array of potential exposure scenarios. In chronic wasting disease...
Prions cause fatal neurodegenerative diseases and exhibit remarkable durability, which engenders a wide array of potential exposure scenarios. In chronic wasting disease of deer, elk, moose, and reindeer and in scrapie of sheep and goats, prions are transmitted via environmental routes and the ability of plants to accumulate and subsequently transmit prions has been hypothesized, but not previously demonstrated. Here, we establish the ability of several crop and other plant species to take up prions via their roots and translocate them to above-ground tissues from various growth media including soils. We demonstrate that plants can accumulate prions in above-ground tissues to levels sufficient to transmit disease after oral ingestion by mice. Our results suggest plants may serve as vectors for prion transmission in the environment-a finding with implications for wildlife conservation, agriculture, and public health.
PubMed: 38077138
DOI: 10.1016/j.isci.2023.108428 -
Neural Regeneration Research Sep 2023In the last decades, the role of the prion protein (PrP) in neurodegenerative diseases has been intensively investigated, initially in prion diseases of humans (e.g.,... (Review)
Review
In the last decades, the role of the prion protein (PrP) in neurodegenerative diseases has been intensively investigated, initially in prion diseases of humans (e.g., Creutzfeldt-Jakob disease) and animals (e.g., scrapie in sheep, chronic wasting disease in deer and elk, or "mad cow disease" in cattle). Templated misfolding of physiological cellular prion protein (PrP) into an aggregation-prone isoform (termed PrP "Scrapie" (PrP)), self-replication and spreading of the latter inside the brain and to peripheral tissues, and the associated formation of infectious proteopathic seeds (termed "prions") are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies. Later, key roles of the correctly folded PrP were identified in more common human brain diseases (such as Alzheimer's disease or Parkinson's disease) associated with the misfolding and/or accumulation of other proteins (such as amyloid-β, tau or α-synuclein, respectively). PrP has also been linked with neuroprotective and regenerative functions, for instance in hypoxic/ischemic conditions such as stroke. However, despite a mixed "bouquet" of suggested functions, our understanding of pathological and, especially, physiological roles played by PrP in the brain and beyond is certainly incomplete. Interactions with various other proteins at the cell surface or within intracellular compartments may account for the functional diversity linked with PrP. Moreover, conserved endogenous proteolytic processing of PrP generates several defined PrP fragments, possibly holding intrinsic functions in physiological and pathological conditions, thus making the "true and complete biology" of this protein more complicated to be elucidated. Here, we focus on one of those released PrP fragments, namely shed PrP (sPrP), generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surface. Similar to other soluble PrP fragments (such as the N1 fragment representing PrP's released N-terminal tail upon the major α-cleavage event) or experimentally employed recombinant PrP, sPrP is being suggested to act neuroprotective in Alzheimer's disease and other protein misfolding diseases. Several lines of evidence on extracellular PrP (fragments) suggest that induction of PrP release could be a future therapeutic option in various brain disorders. Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM10, based on ligands binding to cell surface PrP, may further set the stage for research into this direction.
PubMed: 36926701
DOI: 10.4103/1673-5374.366496