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1
Monzón, Marta. "Morphological Changes of Glia in Prion and a Prion-Like Disorder". Alzheimer’s & Neurodegenerative Diseases 2, n.º 1 (5 de mayo de 2016): 1–4. http://dx.doi.org/10.24966/and-9608/100005.
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Jellinger, Kurt A., Gregor K. Wenning y Nadia Stefanova. "Is Multiple System Atrophy a Prion-like Disorder?" International Journal of Molecular Sciences 22, n.º 18 (18 de septiembre de 2021): 10093. http://dx.doi.org/10.3390/ijms221810093.
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Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions (GCIs) mainly involving oligodendroglia and to a lesser extent neurons, inducing a multisystem neurodegeneration, glial activation, and widespread demyelinization. The neuronal αSyn pathology of MSA has molecular properties different from Lewy bodies in Parkinson’s disease (PD), both of which could serve as a pool of αSyn (prion) seeds that could initiate and drive the pathogenesis of synucleinopathies. The molecular cascade leading to the “prion-like” transfer of “strains” of aggregated αSyn contributing to the progression of the disease is poorly understood, while some presented evidence that MSA is a prion disease. However, this hypothesis is difficult to reconcile with postmortem analysis of human brains and the fact that MSA-like pathology was induced by intracerebral inoculation of human MSA brain homogenates only in homozygous mutant 53T mice, without production of disease-specific GCIs, or with replication of MSA prions in primary astrocyte cultures from transgenic mice expressing human αSyn. Whereas recent intrastriatal injection of Lewy body-derived or synthetic human αSyn fibrils induced PD-like pathology including neuronal αSyn aggregates in macaques, no such transmission of αSyn pathology in non-human primates by MSA brain lysate has been reported until now. Given the similarities between αSyn and prions, there is a considerable debate whether they should be referred to as “prions”, “prion-like”, “prionoids”, or something else. Here, the findings supporting the proposed nature of αSyn as a prion and its self-propagation through seeding as well as the transmissibility of neurodegenerative disorders are discussed. The proof of disease causation rests on the concordance of scientific evidence, none of which has provided convincing evidence for the classification of MSA as a prion disease or its human transmission until now.
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Murakami, Tomoaki, Yasuo Inoshima y Naotaka Ishiguro. "Systemic AA amyloidosis as a prion-like disorder". Virus Research 207 (septiembre de 2015): 76–81. http://dx.doi.org/10.1016/j.virusres.2014.12.019.
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Garcés, Moisés, M. Isabel Guijarro, Antonia Vargas, Juan J. Badiola y Marta Monzón. "Neuroglial patterns are shared by cerebella from prion and prion-like disorder affected patients". Mechanisms of Ageing and Development 184 (diciembre de 2019): 111176. http://dx.doi.org/10.1016/j.mad.2019.111176.
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Ma, Jiyan, Jingjing Zhang y Runchuan Yan. "Recombinant Mammalian Prions: The “Correctly” Misfolded Prion Protein Conformers". Viruses 14, n.º 9 (31 de agosto de 2022): 1940. http://dx.doi.org/10.3390/v14091940.
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Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of misfolded recPrP conformers have been generated, but despite their seeding capability, many of them have failed to elicit a fatal neurodegenerative disorder in wild-type animals like a naturally occurring prion. The application of the protein misfolding cyclic amplification technique and the inclusion of non-protein cofactors in the reaction mixture have led to the generation of authentic recombinant prions that fully recapitulate the characteristics of native prions. Together, these studies reveal that recPrP can stably exist in a variety of misfolded conformations and when inoculated into wild-type animals, misfolded recPrP conformers cause a wide range of outcomes, from being completely innocuous to lethal. Since all these recPrP conformers possess seeding capabilities, these results clearly suggest that seeding activity alone is not equivalent to prion activity. Instead, authentic prions are those PrP conformers that are not only heritable (the ability to seed the conversion of normal PrP) but also pathogenic (the ability to cause fatal neurodegeneration). The knowledge gained from the studies of the recombinant prion is important for us to understand the pathogenesis of prion disease and the roles of misfolded proteins in other neurodegenerative disorders.
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Harrison, Paul M. "Variable absorption of mutational trends by prion-forming domains during Saccharomycetes evolution". PeerJ 8 (6 de agosto de 2020): e9669. http://dx.doi.org/10.7717/peerj.9669.
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Prions are self-propagating alternative states of protein domains. They are linked to both diseases and functional protein roles in eukaryotes. Prion-forming domains in Saccharomyces cerevisiae are typically domains with high intrinsic protein disorder (i.e., that remain unfolded in the cell during at least some part of their functioning), that are converted to self-replicating amyloid forms. S. cerevisiae is a member of the fungal class Saccharomycetes, during the evolution of which a large population of prion-like domains has appeared. It is still unclear what principles might govern the molecular evolution of prion-forming domains, and intrinsically disordered domains generally. Here, it is discovered that in a set of such prion-forming domains some evolve in the fungal class Saccharomycetes in such a way as to absorb general mutation biases across millions of years, whereas others do not, indicating a spectrum of selection pressures on composition and sequence. Thus, if the bias-absorbing prion formers are conserving a prion-forming capability, then this capability is not interfered with by the absorption of bias changes over the duration of evolutionary epochs. Evidence is discovered for selective constraint against the occurrence of lysine residues (which likely disrupt prion formation) in S. cerevisiae prion-forming domains as they evolve across Saccharomycetes. These results provide a case study of the absorption of mutational trends by compositionally biased domains, and suggest methodology for assessing selection pressures on the composition of intrinsically disordered regions.
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Marciniuk, Kristen, Ryan Taschuk y Scott Napper. "Evidence for Prion-Like Mechanisms in Several Neurodegenerative Diseases: Potential Implications for Immunotherapy". Clinical and Developmental Immunology 2013 (2013): 1–20. http://dx.doi.org/10.1155/2013/473706.
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Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.
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Olanow, C. Warren y Patrik Brundin. "Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?" Movement Disorders 28, n.º 1 (enero de 2013): 31–40. http://dx.doi.org/10.1002/mds.25373.
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Chauhan, Aneesha y Alexander F. Jeans. "Is Parkinson’s Disease Truly a Prion-Like Disorder? An Appraisal of Current Evidence". Neurology Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/345285.
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Parkinson’s disease (PD) is the world’s second most common neurodegenerative disease and most common movement disorder. Characterised by a loss of dopaminergic neurons and the development of intraneuronal inclusions known as Lewy bodies, it has classically been thought of as a cell-autonomous disease. However, in 2008, two groups reported the startling observation of Lewy bodies within embryonic neuronal grafts transplanted into PD patients little more than a decade previously, suggesting that PD pathology can be propagated to neighbouring cells and calling basic assumptions of our understanding of the disease into question. Subsequent research has largely served to confirm this interpretation, pointing towards a prion-like intercellular transfer of misfoldedα-synuclein, the main component of Lewy bodies, as central to PD. This shift in thinking offers a revolutionary approach to PD treatment, potentially enabling a transition from purely symptomatic therapy to direct targeting of the pathology that drives disease progression. In this short review, we appraise current experimental support for PD as a prion-like disease, whilst highlighting areas of controversy or inconsistency which must be resolved. We also offer a brief discussion of the therapeutic implications of these discoveries.
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Won, Sae-Young, Yong-Chan Kim, Kyoungtag Do y Byung-Hoon Jeong. "Absence of Strong Genetic Linkage Disequilibrium between Single Nucleotide Polymorphisms (SNPs) in the Prion Protein Gene (PRNP) and the Prion-Like Protein Gene (PRND) in the Horse, a Prion-Resistant Species". Genes 11, n.º 5 (7 de mayo de 2020): 518. http://dx.doi.org/10.3390/genes11050518.
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Prion disease is a fatal neurodegenerative disorder caused by a deleterious prion protein (PrPSc). However, prion disease has not been reported in horses during outbreaks of transmissible spongiform encephalopathies (TSEs) in various animals in the UK. In previous studies, single nucleotide polymorphisms (SNPs) in the prion protein gene (PRNP) have been significantly associated with susceptibility to prion disease, and strong linkage disequilibrium (LD) between PRNP and prion-like protein gene (PRND) SNPs has been identified in prion disease-susceptible species. On the other hand, weak LD values have been reported in dogs, a prion disease-resistant species. In this study, we investigated SNPs in the PRND gene and measured the LD values between the PRNP and PRND SNPs and the impact of a nonsynonymous SNP found in the horse PRND gene. To identify SNPs in the PRND gene, we performed direct sequencing of the PRND gene. In addition, to assess whether the weak LD value between the PRNP and PRND SNPs is a characteristic of prion disease-resistant animals, we measured the LD value between the PRNP and PRND SNPs using D’ and r2 values. Furthermore, we evaluated the impact of a nonsynonymous SNP in the Doppel protein with PolyPhen-2, PROVEAN, and PANTHER. We observed two novel SNPs, c.331G > A (A111T) and c.411G > C. The genotype and allele frequencies of the c.331G > A (A111T) and c.411G > C SNPs were significantly different between Jeju, Halla, and Thoroughbred horses. In addition, we found a total of three haplotypes: GG, AG, and GC. The GG haplotype was the most frequently observed in Jeju and Halla horses. Furthermore, the impact of A111T on the Doppel protein was predicted to be benign by PolyPhen-2, PROVEAN, and PANTHER. Interestingly, a weak LD value between the PRNP and PRND SNPs was found in the horse, a prion disease-resistant animal. To the best of our knowledge, these results suggest that a weak LD value could be one feature of prion disease-resistant animals.
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Chen, Merry, Julie Vincent, Alexis Ezeanii, Saurabh Wakade, Shobha Yerigenahally y Danielle E. Mor. "Heparan sulfate proteoglycans mediate prion-like α-synuclein toxicity in Parkinson’s in vivo models". Life Science Alliance 5, n.º 11 (5 de julio de 2022): e202201366. http://dx.doi.org/10.26508/lsa.202201366.
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Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the central nervous system in a prion-like manner, yet the mechanisms of α-synuclein transmission and neurotoxicity remain poorly understood. Animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first Caenorhabditis elegans models in which feeding with α-synuclein preformed fibrils (PFFs) induces dopaminergic neurodegeneration, prion-like seeding of aggregation of human α-synuclein expressed in the host, and an associated motor decline. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, or other enzymes involved in heparan sulfate proteoglycan synthesis, protected against PFF-induced α-synuclein aggregation, motor dysfunction, and dopamine neuron degeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.
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Pradnya D Jadhav, Vaibhav V Kakade y Aniket E Indrale. "The review on: “Creutzfeldt-Jakob disease”". International Journal of Research in Pharmaceutical Sciences 13, n.º 1 (21 de marzo de 2022): 50–56. http://dx.doi.org/10.26452/ijrps.v13i1.19.
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This review will explore the information about Creutzfeldt -Jakob disease (CJD), which is the human prion disease. CJD is a rare brain disorder and rapidly progressive. CJD belongs to the family of human prion disease, which is caused by misfolded, transmissible infections particles, or prions. Transmissible spongiform encephalopathy (TSEs), also known as prion disease. Spongiform refers to the characteristic appearance of infected brains. CJD affects about one person in every one million people per year worldwide. CJD is a fatal neurodegenerative disorder which is having a higher mortality rate. CJD usually appears in later life and has a high incubation period but become rapidly progressive once clinically symptoms begin. CJD exist in three major groups sporadic CJD (sCJD), Acquired CJD, and Genetic CJD. The sporadic form generally affects the late middle age or elderly persons (Mean age of 67 years). Most people with clinically diagnosed CJD die within a year. Other neurodegenerative illness like Alzheimer's disease involves the deposition of an aberrantly folded protein: although CJD is transmissible. There is no specific treatment for CJD except for supportive care. The arrangement of different clinicians and surveillance programs can maintain awareness of CJD to control the future incidence of its transmission.
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Kujawska, Małgorzata y Jadwiga Jodynis-Liebert. "What Is the Evidence that Parkinson’s Disease Is a Prion Disorder, Which Originates in the Gut?" International Journal of Molecular Sciences 19, n.º 11 (12 de noviembre de 2018): 3573. http://dx.doi.org/10.3390/ijms19113573.
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Parkinson’s disease (PD) is a neurodegenerative disorder resulting from degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). PD is characterized by motor dysfunctions as well as gastrointestinal symptoms and mental impairment. The pathological hallmark of PD is an accumulation of misfolded α-synuclein aggregates within the brain. The etiology of PD and related synucleinopathy is poorly understood, but recently, the hypothesis that α-synuclein pathology spreads in a prion-like fashion originating in the gut has gained much scientific attention. A crucial clue was the appearance of constipation before the onset of motor symptoms, gut dysbiosis and synucleinopathy in PD patients. Another line of evidence, demonstrating accumulation of α-synuclein within the peripheral autonomic nervous system (PANS), including the enteric nervous system (ENS), and the dorsal motor nucleus of the vagus (DMV) support the concept that α-synuclein can spread from the ENS to the brain by the vagus nerve. The decreased risk of PD following truncal vagotomy supports this. The convincing evidence of the prion-like behavior of α-synuclein came from postmortem observations that pathological α-synuclein inclusions appeared in healthy grafted neurons. In this review, we summarize the available data from human subjects’ research and animal experiments, which seem to be the most suggestive for explaining the hypotheses.
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Chiesa, Roberto, Pedro Piccardo, Elena Quaglio, Bettina Drisaldi, San Ling Si-Hoe, Masaki Takao, Bernardino Ghetti y David A. Harris. "Molecular Distinction between Pathogenic and Infectious Properties of the Prion Protein". Journal of Virology 77, n.º 13 (1 de julio de 2003): 7611–22. http://dx.doi.org/10.1128/jvi.77.13.7611-7622.2003.
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ABSTRACT Tg(PG14) mice express a prion protein (PrP) with a nine-octapeptide insertion associated with a human familial prion disease. These animals spontaneously develop a fatal neurodegenerative disorder characterized by ataxia, neuronal apoptosis, and accumulation in the brain of an aggregated and weakly protease-resistant form of mutant PrP (designated PG14spon). Brain homogenates from Tg(PG14) mice fail to transmit disease after intracerebral inoculation into recipient mice, indicating that PG14spon, although pathogenic, is distinct from PrPSc, the infectious form of PrP. In contrast, inoculation of Tg(PG14) mice with exogenous prions of the RML strain induces accumulation of PG14RML, a PrPSc form of the mutant protein that is infectious and highly protease resistant. Like PrPSc, both PG14spon and PG14RML display conformationally masked epitopes in the central and octapeptide repeat regions. However, these two forms differ profoundly in their oligomeric states, with PG14RML aggregates being much larger and more resistant to dissociation. Our analysis provides new molecular insight into an emerging puzzle in prion biology, the discrepancy between the infectious and neurotoxic properties of PrP.
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Hennig, Sven, Geraldine Kong, Taro Mannen, Agata Sadowska, Simon Kobelke, Amanda Blythe, Gavin J. Knott et al. "Prion-like domains in RNA binding proteins are essential for building subnuclear paraspeckles". Journal of Cell Biology 210, n.º 4 (17 de agosto de 2015): 529–39. http://dx.doi.org/10.1083/jcb.201504117.
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Prion-like domains (PLDs) are low complexity sequences found in RNA binding proteins associated with the neurodegenerative disorder amyotrophic lateral sclerosis. Recently, PLDs have been implicated in mediating gene regulation via liquid-phase transitions that drive ribonucleoprotein granule assembly. In this paper, we report many PLDs in proteins associated with paraspeckles, subnuclear bodies that form around long noncoding RNA. We mapped the interactome network of paraspeckle proteins, finding enrichment of PLDs. We show that one protein, RBM14, connects key paraspeckle subcomplexes via interactions mediated by its PLD. We further show that the RBM14 PLD, as well as the PLD of another essential paraspeckle protein, FUS, is required to rescue paraspeckle formation in cells in which their endogenous counterpart has been knocked down. Similar to FUS, the RBM14 PLD also forms hydrogels with amyloid-like properties. These results suggest a role for PLD-mediated liquid-phase transitions in paraspeckle formation, highlighting this nuclear body as an excellent model system for understanding the perturbation of such processes in neurodegeneration.
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Tarnacka, Beata, Anna Jopowicz y Maria Maślińska. "Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions". International Journal of Molecular Sciences 22, n.º 15 (22 de julio de 2021): 7820. http://dx.doi.org/10.3390/ijms22157820.
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Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and “prion-like disease”, amyotrophic lateral sclerosis, Huntington’s disease, Friedreich’s ataxia, and depression.
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Jones, David T., Ryan A. Townley, Jonathan Graff-Radford, Hugo Botha, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, Val J. Lowe y Bradley F. Boeve. "Amyloid- and tau-PET imaging in a familial prion kindred". Neurology Genetics 4, n.º 6 (diciembre de 2018): e290. http://dx.doi.org/10.1212/nxg.0000000000000290.
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ObjectiveTo study the in vivo binding properties of 18F-AV-1451 (tau-PET) and Pittsburgh compound B (PiB-PET) in a unique kindred with a familial prion disorder known to produce amyloid plaques composed of prion protein alongside Alzheimer disease (AD)–like tau tangles.MethodsA case series of 4 symptomatic family members with the 12-octapeptide repeat insertion in the PRNP gene were imaged with 3T MRI, PiB-PET, and tau-PET in their fourth decade of life.ResultsThere was significant neocortical uptake of the tau-PET tracer in all 4 familial prion cases. However, PiB-PET images did not demonstrate abnormally elevated signal in neocortical or cerebellar regions for any of the patients.ConclusionsIn vivo detection of molecular hallmarks of neurodegenerative diseases will be a prerequisite to well-conducted therapeutic trials. Understanding the in vivo behavior of these PET biomarkers in the setting of various neurodegenerative processes is imperative to their proper use in such trials and for research studies focused on the basic neurobiology of neurodegeneration. This study supports the high specificity of neocortical 18F-AV-1451 binding to AD-like tau and the lack of PiB binding to PrP plaques. It is uncertain how early in the disease course tau pathology appears in the brains of individuals who carry this PRNP gene mutation or how it evolves throughout the disease course, but future longitudinal 18F-AV-1451 imaging of symptomatic and asymptomatic individuals in this kindred will help address these uncertainties.
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Westermark, Per y Gunilla T. Westermark. "Reflections on amyloidosis in Papua New Guinea". Philosophical Transactions of the Royal Society B: Biological Sciences 363, n.º 1510 (27 de noviembre de 2008): 3701–5. http://dx.doi.org/10.1098/rstb.2008.0073.
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The amyloidoses comprise a heterogeneous group of diseases in which 1 out of more than 25 human proteins aggregates into characteristic beta-sheet fibrils with some unique properties. Aggregation is nucleation dependent. Among the known amyloid-forming constituents is the prion protein, well known for its ability to transmit misfolding and disease from one individual to another. There is increasing evidence that other amyloid forms also may be transmissible but only if certain prerequisites are fulfilled. One of these forms is systemic AA-amyloidosis in which an acute-phase reactant, serum AA, is over-expressed and, possibly after cleavage, aggregates into amyloid fibrils, causing disease. In a mouse model, this disorder can easily be transmitted from one animal to another both by intravenous and oral routes. Also, synthetic amyloid-like fibrils made from defined small peptides have this property, indicating a prion-like transmission mechanism. Even some fibrils occurring in the environment can transmit AA-amyloidosis in the murine model. AA-amyloidosis is particularly common in certain areas of Papua New Guinea, probably due to the endemicity of malaria and perhaps genetic predisposition. Now, when kuru is disappearing, more interest should be focused on the potentially lethal systemic AA-amyloidosis.
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Longhena, Francesca, Gaia Faustini, Cristina Missale, Marina Pizzi, PierFranco Spano y Arianna Bellucci. "The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy". Neural Plasticity 2017 (2017): 1–15. http://dx.doi.org/10.1155/2017/5012129.
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Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson’s disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related toα-synuclein deposition at synaptic sites. Indeed,α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate thatα-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillaryα-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence ofα-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration.
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Chmielarz, Piotr y Mart Saarma. "Neurotrophic factors for disease-modifying treatments of Parkinson's disease: gaps between basic science and clinical studies". Pharmacological Reports 72, n.º 5 (22 de julio de 2020): 1195–217. http://dx.doi.org/10.1007/s43440-020-00120-3.
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Abstract Background Neurotrophic factors are endogenous proteins promoting the survival of different neural cells. Therefore, they elicited great interest as a possible treatment for neurodegenerative disorders, including Parkinson’s Disease (PD). PD is the second most common neurodegenerative disorder, scientifically characterized more than 200 years ago and initially linked with motor abnormalities. Currently, the disease is viewed as a highly heterogeneous, progressive disorder with a long presymptomatic phase, and both motor and non-motor symptoms. Presently only symptomatic treatments for PD are available. Neurohistopathological changes of PD affected brains have been described more than 100 years ago and characterized by the presence of proteinaceous inclusions known as Lewy bodies and degeneration of dopamine neurons. Despite more than a century of investigations, it has remained unclear why dopamine neurons die in PD. Methods This review summarizes literature data from preclinical studies and clinical trials of neurotrophic factor based therapies for PD and discuss it from the perspective of the current understanding of PD biology. Results Newest data point towards dysfunctions of mitochondria, autophagy-lysosomal pathway, unfolded protein response and prion protein-like spreading of misfolded alpha-synuclein that is the major component of Lewy bodies. Yet, the exact chain of events leading to the demise of dopamine neurons is unclear and perhaps different in subpopulations of patients. Conclusions Gaps in our understanding of underlying disease etiology have hindered our attempts to find treatments able to slow down the progression of PD. Graphic abstract
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Tamaki, Yoshitaka, Jay P. Ross, Paria Alipour, Charles-Étienne Castonguay, Boting Li, Helene Catoire, Daniel Rochefort et al. "Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids". PLOS Genetics 19, n.º 2 (6 de febrero de 2023): e1010606. http://dx.doi.org/10.1371/journal.pgen.1010606.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.
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Zhu, Seng, Saïda Abounit, Carsten Korth y Chiara Zurzolo. "Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine". Open Biology 7, n.º 3 (marzo de 2017): 160328. http://dx.doi.org/10.1098/rsob.160328.
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The disrupted-in-schizophrenia 1 ( DISC1 ) gene was identified as a genetic risk factor for chronic mental illnesses (CMI) such as schizophrenia, bipolar disorder and severe recurrent depression. Insoluble aggregated DISC1 variants were found in the cingular cortex of sporadic, i.e. non-genetic, CMI patients. This suggests protein pathology as a novel, additional pathogenic mechanism, further corroborated in a recent transgenic rat model presenting DISC1 aggregates. Since the potential role of aggregation of DISC1 in sporadic CMI is unknown, we investigated whether DISC1 undergoes aggregation in cell culture and could spread between neuronal cells in a prion-like manner, as shown for amyloid proteins in neurodegenerative diseases. Co-culture experiments between donor cells forming DISC1 aggregates and acceptor cells showed that 4.5% of acceptor cells contained donor-derived DISC1 aggregates, thus indicating an efficient transfer in vitro . DISC1 aggregates were found inside tunnelling nanotubes (TNTs) and transfer was enhanced by increasing TNT formation and notably by dopamine treatment, which also induces DISC1 aggregation. These data indicate that DISC1 aggregates can propagate between cells similarly to prions, thus providing some molecular basis for the role of protein pathology in CMI.
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Pintado-Grima, Carlos, Oriol Bárcenas, Andrea Bartolomé-Nafría, Marc Fornt-Suñé, Valentín Iglesias, Javier Garcia-Pardo y Salvador Ventura. "A Review of Fifteen Years Developing Computational Tools to Study Protein Aggregation". Biophysica 3, n.º 1 (18 de enero de 2023): 1–20. http://dx.doi.org/10.3390/biophysica3010001.
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The presence of insoluble protein deposits in tissues and organs is a hallmark of many human pathologies. In addition, the formation of protein aggregates is considered one of the main bottlenecks to producing protein-based therapeutics. Thus, there is a high interest in rationalizing and predicting protein aggregation. For almost two decades, our laboratory has been working to provide solutions for these needs. We have traditionally combined the core tenets of both bioinformatics and wet lab biophysics to develop algorithms and databases to study protein aggregation and its functional implications. Here, we review the computational toolbox developed by our lab, including programs for identifying sequential or structural aggregation-prone regions at the individual protein and proteome levels, engineering protein solubility, finding and evaluating prion-like domains, studying disorder-to-order protein transitions, or categorizing non-conventional amyloid regions of polar nature, among others. In perspective, the succession of the tools we describe illustrates how our understanding of the protein aggregation phenomenon has evolved over the last fifteen years.
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Bhopatkar, Anukool A., Vladimir N. Uversky y Vijayaraghavan Rangachari. "Granulins modulate liquid–liquid phase separation and aggregation of the prion-like C-terminal domain of the neurodegeneration-associated protein TDP-43". Journal of Biological Chemistry 295, n.º 8 (6 de enero de 2020): 2506–19. http://dx.doi.org/10.1074/jbc.ra119.011501.
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TAR DNA-binding protein 43 (TDP-43) has emerged as a key player in many neurodegenerative pathologies, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Hallmarks of both FTLD and ALS are the toxic cytoplasmic inclusions of the prion-like C-terminal fragments of TDP-43 CTD (TDP-43 C-terminal domain), formed upon proteolytic cleavage of full-length TDP-43 in the nucleus and subsequent transport to the cytoplasm. Both full-length TDP-43 and its CTD are also known to form stress granules by coacervating with RNA in the cytoplasm during stress and may be involved in these pathologies. Furthermore, mutations in the PGRN gene, leading to haploinsufficiency and diminished function of progranulin (PGRN) protein, are strongly linked to FTLD and ALS. Recent reports have indicated that proteolytic processing of PGRN to smaller protein modules called granulins (GRNs) contributes to FTLD and ALS progression, with specific GRNs exacerbating TDP-43–induced cytotoxicity. Here we investigated the interactions between the proteolytic products of both TDP-43 and PGRN. Based on structural disorder and charge distributions, we hypothesized that GRN-3 and GRN-5 could interact with the TDP-43 CTD. We show that, under both reducing and oxidizing conditions, GRN-3 and GRN-5 interact with and differentially modulate TDP-43 CTD aggregation and/or liquid–liquid phase separation in vitro. GRN-3 promoted insoluble aggregates of the TDP-43 CTD while GRN-5 mediated liquid–liquid phase separation. These results constitute the first observation of an interaction between GRNs and TDP-43, suggesting a mechanism by which attenuated PGRN function could lead to familial FTLD or ALS.
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Weiß, Alexander, Andreu Matamoros-Angles, Fanni Annamária Boros, Philipp Arnold y Friederike Zunke. "Extracellular vesicles – upcoming biomarkers in Parkinson's disease's biofluids". Novel methods and insights: A profound look at the function of extracellular vesicles 4, n.º 1 (10 de octubre de 2022): 45–51. http://dx.doi.org/10.47184/tev.2022.01.06.
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The search of a biomarker for an early detection of neurodegenerative diseases is one of the biggest challenges of our times. The second most common neurodegenerative disorder Parkinson's disease (PD) is characterized by misfolded alpha-synuclein (a-syn) aggregates within the central nervous system (CNS). Currently, definitive PD diagnosis still requires post-mortem brain examination. As a result, the misdiagnosis of PD based only on clinical symptoms and delayed diagnosis in advanced stages cannot be excluded. Since a-syn aggregates abnormally, it might be an interesting candidate for a biomarker for PD. Lately, extracellular vesicles (EVs) have emerged as potential biomarker in biofluids since accumulating evidence suggests that their content reflects the pathophysiological alterations occurring in their host cells. Interestingly, EVs can cross the blood-brain barrier (BBB) and thus carry information from the CNS to the periphery and vice versa. EVs seem to play a role in other neurodegenerative disorders such as Alzheimer's and prion disease, where they have also shown certain diagnostic potential. For instance, EV isolation protocols have been described to isolate brain-derived EVs from blood samples, increasing their biomarker potential in neurodegenerative disorders. The results published for PD to date are promising: pathology-associated a-syn forms are found in blood-derived EVs, although the underlying mechanisms of formation and release of a-syn-loaded EVs remain unknown. Interestingly, a-syn level correlate with the disease stage, which underlines the importance of neuronal EVs in disease monitoring. Further research extends to other biofluids, like urine, saliva, and cerebrospinal fluid, where EVs can also be found, opening multiple opportunities for more reliable PD diagnosis.
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Cuevas, Eva P., Alberto Rodríguez-Fernández, Valle Palomo, Ana Martínez y Ángeles Martín-Requero. "TDP-43 Pathology and Prionic Behavior in Human Cellular Models of Alzheimer’s Disease Patients". Biomedicines 10, n.º 2 (5 de febrero de 2022): 385. http://dx.doi.org/10.3390/biomedicines10020385.
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Alzheimer’s disease (AD) is a neurodegenerative disorder for which there is currently no effective treatment. Despite advances in the molecular pathology of the characteristic histopathological markers of the disease (tau protein and β-amyloid), their translation to the clinic has not provided the expected results. Increasing evidences have demonstrated the presence of aggregates of TDP-43 (TAR DNA binding protein 43) in the postmortem brains of patients diagnosed with AD. The present research is focused on of the study of the pathological role of TDP-43 in AD. For this purpose, immortalized lymphocytes samples from patients diagnosed with different severity of sporadic AD were used and the TDP-43 pathology was analyzed against controls, looking for differences in their fragmentation, phosphorylation and cellular location using Western blot and immunocytochemical techniques. The results revealed an increase in TDP-43 fragmentation, as well as increased phosphorylation and aberrant localization of TDP-43 in the cytosolic compartment of lymphocytes of patients diagnosed with severe AD. Moreover, a fragment of approximately 25 KD was found in the extracellular medium of cells derived from severe AD individuals that seem to have prion-like characteristics. We conclude that TDP-43 plays a key role in AD pathogenesis and its cell to cell propagation.
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Angot, Elodie, Jennifer A. Steiner, Christian Hansen, Jia-Yi Li y Patrik Brundin. "Are synucleinopathies prion-like disorders?" Lancet Neurology 9, n.º 11 (noviembre de 2010): 1128–38. http://dx.doi.org/10.1016/s1474-4422(10)70213-1.
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Chapman, A. H. y Djalma Vieira e. Silva. "Creutzfeldt-Jakob disease a case report, with special attention to the electroencephalogram in this disorder and to its possible relationships to kuru, scrapie and «mad cow disease»". Arquivos de Neuro-Psiquiatria 51, n.º 2 (junio de 1993): 258–66. http://dx.doi.org/10.1590/s0004-282x1993000200020.
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A case of Creutzfeldt-Jakob disease in a 58-year-old Brazillian cattle rancher and businessman is presented. The EEG was normal, which is consistent with the fact that it was made during the first half of his illness; in a later stage suppression of normal rhythms by slow moderate voltage waves would be expected. The resemblances of kuru, scrapie and "mad cow disease» to C-J disease are discussed. In each of these 4 illnesses the patient or affected animal (scrapie and «mad cow disease") (a) has a widespread spongiform encephalopathy and consequent dementia, myoclonic epilepsy and cerebellar and corticospinal symptoms, (b) Each illness is caused by a virus (or virus-like organism called a PrP or prion) which is unusually resistant to heat and entirely resistant to ultraviolet light and x-rays, (c) This causative agent can be transmitted to other mammals by intracerebral injection or, in the proved cases of 3 of them, by the oral route. Unresolved questions about C-J disease include the following: Are C-J disease, kuru, scrapie and "mad cow disease" essentially similar illnesses caused by the same virus or by subtle variants of it? What is the incubation period of C-J disease, and does its virus exist for long periods of time in some asymptomatic persons, some of whom may never become neurologically ill? How does this virus enter the bodies of most persons with C-J disease, and why does the clinical disease characteristically occur only in middle age?
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Cherry, Pearl y Sabine Gilch. "The Role of Vesicle Trafficking Defects in the Pathogenesis of Prion and Prion-Like Disorders". International Journal of Molecular Sciences 21, n.º 19 (23 de septiembre de 2020): 7016. http://dx.doi.org/10.3390/ijms21197016.
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Prion diseases are fatal and transmissible neurodegenerative diseases in which the cellular form of the prion protein ‘PrPc’, misfolds into an infectious and aggregation prone isoform termed PrPSc, which is the primary component of prions. Many neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases, such as Huntington’s disease, are considered prion-like disorders because of the common characteristics in the propagation and spreading of misfolded proteins that they share with the prion diseases. Unlike prion diseases, these are non-infectious outside experimental settings. Many vesicular trafficking impairments, which are observed in prion and prion-like disorders, favor the accumulation of the pathogenic amyloid aggregates. In addition, many of the vesicular trafficking impairments that arise in these diseases, turn out to be further aggravating factors. This review offers an insight into the currently known vesicular trafficking defects in these neurodegenerative diseases and their implications on disease progression. These findings suggest that these impaired trafficking pathways may represent similar therapeutic targets in these classes of neurodegenerative disorders.
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Ali, Addison, Kristeen Pareja y Tara Tracy. "Acetylation of Tau Induces Alzheimer's Disease-Associated Tau in Transgenic Mice". Innovation in Aging 5, Supplement_1 (1 de diciembre de 2021): 958. http://dx.doi.org/10.1093/geroni/igab046.3457.
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Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by neurofibrillary tangles (NFTs) and amyloid beta plaques. These NFTs are made up of aggregated tau proteins. Tau is involved in stabilizing microtubules and does not usually display aggregation. Acetylation of tau protein causes an increase in tau aggregation but its role in AD progression is still not well understood. I hypothesized that enhanced acetylated tau results in an increase in AD-like tau pathology. To test this, a murine prion promoter-tauKQ transgene was injected into the mouse fertilized oocyte. The tauKQ mutation alters lysine to glutamine to mimic acetylation of tau. Nontransgenic mice were used as controls. AT8 and GT-38 antibodies were used in immunohistochemistry (IHC) to target phosphorylated tau and AD-associated tau, respectively. GT-38 is conformation-dependent and requires 3R and 4R tau isoforms which makes it specific to AD. Through immunofluorescence, increased phosphorylated tau was observed in the hippocampus of the tauKQ mice compared to the nontransgenic mice. I focused on the dentate gyrus, CA1 region, and the mossy fibers of the CA3 region since they are involved in many memory processes. Through chromogenic IHC, the tauKQ mice exhibited more 3R+4R tau isoform pathology in the mossy fibers than the nontransgenic mice. This data suggests that an acetylation mimic is sufficient to stimulate an abundance of AD-related tau pathology in transgenic mice which is consistent with my hypothesis. The tauKQ mouse model can assist in understanding the role of tau acetylation and tau progression for AD.
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Wilson, Rona, Declan King, Nora Hunter, Wilfred Goldmann y Rona M. Barron. "Characterization of an unusual transmissible spongiform encephalopathy in goat by transmission in knock-in transgenic mice". Journal of General Virology 94, n.º 8 (1 de agosto de 2013): 1922–32. http://dx.doi.org/10.1099/vir.0.051706-0.
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Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative disorder of cattle, and its transmission to humans through contaminated food is thought to be the cause of the variant form of Creutzfeldt–Jakob disease. BSE is believed to have spread from the recycling in cattle of ruminant tissue in meat and bone meal (MBM). However, during this time, sheep and goats were also exposed to BSE-contaminated MBM. Both sheep and goats are experimentally susceptible to BSE, and while there have been no reported natural BSE cases in sheep, two goat BSE field cases have been documented. While cases of BSE are rare in small ruminants, the existence of scrapie in both sheep and goats is well established. In the UK, during 2006–2007, a serious outbreak of clinical scrapie was detected in a large dairy goat herd. Subsequently, 200 goats were selected for post-mortem examination, one of which showed biochemical and immunohistochemical features of the disease-associated prion protein (PrPTSE) which differed from all other infected goats. In the present study, we investigated this unusual case by performing transmission bioassays into a panel of mouse lines. Following characterization, we found that strain properties such as the ability to transmit to different mouse lines, lesion profile pattern, degree of PrP deposition in the brain and biochemical features of this unusual goat case were neither consistent with goat BSE nor with a goat scrapie herdmate control. However, our results suggest that this unusual case has BSE-like properties and highlights the need for continued surveillance.
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Pineau, Hailey y Valerie Sim. "POSCAbilities: The Application of the Prion Organotypic Slice Culture Assay to Neurodegenerative Disease Research". Biomolecules 10, n.º 7 (20 de julio de 2020): 1079. http://dx.doi.org/10.3390/biom10071079.
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Prion diseases are fatal, transmissible neurodegenerative disorders whose pathogenesis is driven by the misfolding, self-templating and cell-to-cell spread of the prion protein. Other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease, share some of these prion-like features, with different aggregation-prone proteins. Consequently, researchers have begun to apply prion-specific techniques, like the prion organotypic slice culture assay (POSCA), to these disorders. In this review we explore the ways in which the prion phenomenon has been used in organotypic cultures to study neurodegenerative diseases from the perspective of protein aggregation and spreading, strain propagation, the role of glia in pathogenesis, and efficacy of drug treatments. We also present an overview of the advantages and disadvantages of this culture system compared to in vivo and in vitro models and provide suggestions for new directions.
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Sarnataro, Daniela. "Attempt to Untangle the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases". International Journal of Molecular Sciences 19, n.º 10 (9 de octubre de 2018): 3081. http://dx.doi.org/10.3390/ijms19103081.
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The misfolding and aggregation of proteins is the neuropathological hallmark for numerous diseases including Alzheimer’s disease, Parkinson’s disease, and prion diseases. It is believed that misfolded and abnormal β-sheets forms of wild-type proteins are the vectors of these diseases by acting as seeds for the aggregation of endogenous proteins. Cellular prion protein (PrPC) is a glycosyl-phosphatidyl-inositol (GPI) anchored glycoprotein that is able to misfold to a pathogenic isoform PrPSc, the causative agent of prion diseases which present as sporadic, dominantly inherited and transmissible infectious disorders. Increasing evidence highlights the importance of prion-like seeding as a mechanism for pathological spread in Alzheimer’s disease and Tauopathy, as well as other neurodegenerative disorders. Here, we report the latest findings on the mechanisms controlling protein folding, focusing on the ER (Endoplasmic Reticulum) quality control of GPI-anchored proteins and describe the “prion-like” properties of amyloid-β and tau assemblies. Furthermore, we highlight the importance of pathogenic assemblies interaction with protein and lipid membrane components and their implications in both prion and Alzheimer’s diseases
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Acquatella-Tran Van Ba, Isabelle, Thibaut Imberdis y Véronique Perrier. "From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases". International Journal of Cell Biology 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/975832.
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Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrPSc, an abnormalβ-sheet-rich form of the cellular prion protein (PrPC) (Prusiner 1982). According to the prion hypothesis, PrPSccan trigger the autocatalytic conversion of PrPCinto PrPSc, presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of “deformed templating” regarding a new mechanism of PrPScformation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease and tauopathies.
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Peggion, Caterina, Maria Sorgato y Alessandro Bertoli. "Prions and Prion-Like Pathogens in Neurodegenerative Disorders". Pathogens 3, n.º 1 (18 de febrero de 2014): 149–63. http://dx.doi.org/10.3390/pathogens3010149.
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Mastrianni, James A. "The Prion Diseases: Creutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker, and Related Disorders". Journal of Geriatric Psychiatry and Neurology 11, n.º 2 (julio de 1998): 78–97. http://dx.doi.org/10.1177/089198879801100206.
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The prion diseases are an interesting group of neurodegenerative disorders for a variety of reasons. The most obvious is their property of transmissibility, but beyond that they constitute a fascinating example of the diversity of disease expression possible from a common etiologic factor. Thought of as “strains” in animals and phenotypes in humans, these varied expressions of prion disease are most likely due to subtle conformational changes in the pathogenic form of the prion protein. These strain-like characteristics are best exemplified in the genetic varieties of human prion disease in which specific mutations are associated with specific phenotypic profiles. This review attempts to highlight the clinical and pathologic features of the prion diseases with a particular focus on the genetic determinants that define the various familial forms and that modify sporadic and iatrogenic forms of the disease.
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Heng, Yang, Yan-Yan Li, Lu Wen, Jia-Qing Yan, Nai-Hong Chen y Yu-He Yuan. "Gastric Enteric Glial Cells: A New Contributor to the Synucleinopathies in the MPTP-Induced Parkinsonism Mouse". Molecules 27, n.º 21 (1 de noviembre de 2022): 7414. http://dx.doi.org/10.3390/molecules27217414.
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Accumulating evidence has shown that Parkinson’s disease (PD) is a systemic disease other than a mere central nervous system (CNS) disorder. One of the most important peripheral symptoms is gastrointestinal dysfunction. The enteric nervous system (ENS) is regarded as an essential gateway to the environment. The discovery of the prion-like behavior of α-synuclein makes it possible for the neurodegenerative process to start in the ENS and spread via the gut-brain axis to the CNS. We first confirmed that synucleinopathies existed in the stomachs of chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mice, as indicated by the significant increase in abnormal aggregated and nitrated α-synuclein in the TH-positive neurons and enteric glial cells (EGCs) of the gastric myenteric plexus. Next, we attempted to clarify the mechanisms in single MPTP-injected mice. The stomach naturally possesses high monoamine oxidase-B (MAO-B) activity and low superoxide dismutase (SOD) activity, making the stomach susceptible to MPTP-induced oxidative stress, as indicated by the significant increase in reactive oxygen species (ROS) in the stomach and elevated 4-hydroxynonenal (4-HNE) in the EGCs after MPTP exposure for 3 h. Additionally, stomach synucleinopathies appear before those of the nigrostriatal system, as determined by Western blotting 12 h after MPTP injection. Notably, nitrated α-synuclein was considerably increased in the EGCs after 3 h and 12 h of MPTP exposure. Taken together, our work demonstrated that the EGCs could be new contributors to synucleinopathies in the stomach. The early-initiated synucleinopathies might further influence neighboring neurons in the myenteric plexus and the CNS. Our results offer a new experimental clue for interpreting the etiology of PD.
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Contiliani, Danyel Fernandes, Yasmin de Araújo Ribeiro, Vitor Nolasco de Moraes y Tiago Campos Pereira. "MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine". Cells 10, n.º 7 (29 de junio de 2021): 1620. http://dx.doi.org/10.3390/cells10071620.
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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.
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Costanzo, Maddalena y Chiara Zurzolo. "The cell biology of prion-like spread of protein aggregates: mechanisms and implication in neurodegeneration". Biochemical Journal 452, n.º 1 (25 de abril de 2013): 1–17. http://dx.doi.org/10.1042/bj20121898.
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The misfolding and aggregation of specific proteins is a common hallmark of many neurodegenerative disorders, including highly prevalent illnesses such as Alzheimer's and Parkinson's diseases, as well as rarer disorders such as Huntington's and prion diseases. Among these, only prion diseases are ‘infectious’. By seeding misfolding of the PrPC (normal conformer prion protein) into PrPSc (abnormal disease-specific conformation of prion protein), prions spread from the periphery of the body to the central nervous system and can also be transmitted between individuals of the same or different species. However, recent exciting data suggest that the transmissibility of misfolded proteins within the brain is a property that goes way beyond the rare prion diseases. Evidence indicates that non-prion aggregates [tau, α-syn (α-synuclein), Aβ (amyloid-β) and Htt (huntingtin) aggregates] can also move between cells and seed the misfolding of their normal conformers. These findings have enormous implications. On the one hand they question the therapeutical use of transplants, and on the other they indicate that it may be possible to bring these diseases to an early arrest by preventing cell-to-cell transmission. To better understand the prion-like spread of these protein aggregates it is essential to identify the underlying cellular and molecular factors. In the present review we analyse and discuss the evidence supporting prion-like spreading of amyloidogenic proteins, especially focusing on the cellular and molecular mechanisms and their significance.
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Scialò, Carlo, Elena De Cecco, Paolo Manganotti y Giuseppe Legname. "Prion and Prion-Like Protein Strains: Deciphering the Molecular Basis of Heterogeneity in Neurodegeneration". Viruses 11, n.º 3 (14 de marzo de 2019): 261. http://dx.doi.org/10.3390/v11030261.
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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-β (Aβ), tau, α-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.
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Herva, Maria Eugenia y Maria Grazia Spillantini. "Parkinson's disease as a member of Prion-like disorders". Virus Research 207 (septiembre de 2015): 38–46. http://dx.doi.org/10.1016/j.virusres.2014.10.016.
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Malinovska, Liliana, Sandra Palm, Kimberley Gibson, Jean-Marc Verbavatz y Simon Alberti. "Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation". Proceedings of the National Academy of Sciences 112, n.º 20 (4 de mayo de 2015): E2620—E2629. http://dx.doi.org/10.1073/pnas.1504459112.
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Many protein-misfolding diseases are caused by proteins carrying prion-like domains. These proteins show sequence similarity to yeast prion proteins, which can interconvert between an intrinsically disordered and an aggregated prion state. The natural presence of prions in yeast has provided important insight into disease mechanisms and cellular proteostasis. However, little is known about prions in other organisms, and it is not yet clear whether the findings in yeast can be generalized. Using bioinformatics tools, we show that Dictyostelium discoideum has the highest content of prion-like proteins of all organisms investigated to date, suggesting that its proteome has a high overall aggregation propensity. To study mechanisms regulating these proteins, we analyze the behavior of several well-characterized prion-like proteins, such as an expanded version of human huntingtin exon 1 (Q103) and the prion domain of the yeast prion protein Sup35 (NM), in D. discoideum. We find that these proteins remain soluble and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic cytosolic aggregates. However, when exposed to conditions that compromise molecular chaperones, these proteins aggregate and become cytotoxic. We show that the disaggregase Hsp101, a molecular chaperone of the Hsp100 family, dissolves heat-induced aggregates and promotes thermotolerance. Furthermore, prion-like proteins accumulate in the nucleus, where they are targeted by the ubiquitin–proteasome system. Our data suggest that D. discoideum has undergone specific adaptations that increase the proteostatic capacity of this organism and allow for an efficient regulation of its prion-like proteome.
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Ritchie, Diane L. y Marcelo A. Barria. "Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?" Biomolecules 11, n.º 2 (2 de febrero de 2021): 207. http://dx.doi.org/10.3390/biom11020207.
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The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.
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Otero, Alicia, Marina Betancor, Hasier Eraña, Natalia Fernández Borges, José J. Lucas, Juan José Badiola, Joaquín Castilla y Rosa Bolea. "Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease". International Journal of Molecular Sciences 22, n.º 1 (5 de enero de 2021): 465. http://dx.doi.org/10.3390/ijms22010465.
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Prion diseases are a group of neurodegenerative disorders that can be spontaneous, familial or acquired by infection. The conversion of the prion protein PrPC to its abnormal and misfolded isoform PrPSc is the main event in the pathogenesis of prion diseases of all origins. In spontaneous prion diseases, the mechanisms that trigger the formation of PrPSc in the central nervous system remain unknown. Several reports have demonstrated that the accumulation of PrPSc can induce endoplasmic reticulum (ER) stress and proteasome impairment from the early stages of the prion disease. Both mechanisms lead to an increment of PrP aggregates in the secretory pathway, which could explain the pathogenesis of spontaneous prion diseases. Here, we investigate the role of ER stress and proteasome impairment during prion disorders in a murine model of spontaneous prion disease (TgVole) co-expressing the UbG76V-GFP reporter, which allows measuring the proteasome activity in vivo. Spontaneously prion-affected mice showed a significantly higher accumulation of the PKR-like ER kinase (PERK), the ER chaperone binding immunoglobulin protein (BiP/Grp78), the ER protein disulfide isomerase (PDI) and the UbG76V-GFP reporter than age-matched controls in certain brain areas. The upregulation of PERK, BiP, PDI and ubiquitin was detected from the preclinical stage of the disease, indicating that ER stress and proteasome impairment begin at early stages of the spontaneous disease. Strong correlations were found between the deposition of these markers and neuropathological markers of prion disease in both preclinical and clinical mice. Our results suggest that both ER stress and proteasome impairment occur during the pathogenesis of spontaneous prion diseases.
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Carlson, George A. y Stanley B. Prusiner. "How an Infection of Sheep Revealed Prion Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders". International Journal of Molecular Sciences 22, n.º 9 (4 de mayo de 2021): 4861. http://dx.doi.org/10.3390/ijms22094861.
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Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived Aβ peptides, tau, and α-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field.
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Polymenidou, Magdalini y Don W. Cleveland. "Prion-like spread of protein aggregates in neurodegeneration". Journal of Experimental Medicine 209, n.º 5 (7 de mayo de 2012): 889–93. http://dx.doi.org/10.1084/jem.20120741.
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Protein misfolding is common to most neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Recent work using animal models with intracellular α-synuclein and tau inclusions adds decisively to a growing body of evidence that misfolded protein aggregates can induce a self-perpetuating process that leads to amplification and spreading of pathological protein assemblies. When coupled with the progressive nature of neurodegeneration, recognition of such cell-to-cell aggregate spread suggests a unifying mechanism underlying the pathogenesis of these disorders.
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Noor, Aneeqa, Saima Zafar y Inga Zerr. "Neurodegenerative Proteinopathies in the Proteoform Spectrum—Tools and Challenges". International Journal of Molecular Sciences 22, n.º 3 (22 de enero de 2021): 1085. http://dx.doi.org/10.3390/ijms22031085.
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Proteinopathy refers to a group of disorders defined by depositions of amyloids within living tissue. Neurodegenerative proteinopathies, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt–Jakob disease, and others, constitute a large fraction of these disorders. Amyloids are highly insoluble, ordered, stable, beta-sheet rich proteins. The emerging theory about the pathophysiology of neurodegenerative proteinopathies suggests that the primary amyloid-forming proteins, also known as the prion-like proteins, may exist as multiple proteoforms that contribute differentially towards the disease prognosis. It is therefore necessary to resolve these disorders on the level of proteoforms rather than the proteome. The transient and hydrophobic nature of amyloid-forming proteins and the minor post-translational alterations that lead to the formation of proteoforms require the use of highly sensitive and specialized techniques. Several conventional techniques, like gel electrophoresis and conventional mass spectrometry, have been modified to accommodate the proteoform theory and prion-like proteins. Several new ones, like imaging mass spectrometry, have also emerged. This review aims to discuss the proteoform theory of neurodegenerative disorders along with the utility of these proteomic techniques for the study of highly insoluble proteins and their associated proteoforms.
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Carroll, James y Bruce Chesebro. "Neuroinflammation, Microglia, and Cell-Association during Prion Disease". Viruses 11, n.º 1 (15 de enero de 2019): 65. http://dx.doi.org/10.3390/v11010065.
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Prion disorders are transmissible diseases caused by a proteinaceous infectious agent that can infect the lymphatic and nervous systems. The clinical features of prion diseases can vary, but common hallmarks in the central nervous system (CNS) are deposition of abnormally folded protease-resistant prion protein (PrPres or PrPSc), astrogliosis, microgliosis, and neurodegeneration. Numerous proinflammatory effectors expressed by astrocytes and microglia are increased in the brain during prion infection, with many of them potentially damaging to neurons when chronically upregulated. Microglia are important first responders to foreign agents and damaged cells in the CNS, but these immune-like cells also serve many essential functions in the healthy CNS. Our current understanding is that microglia are beneficial during prion infection and critical to host defense against prion disease. Studies indicate that reduction of the microglial population accelerates disease and increases PrPSc burden in the CNS. Thus, microglia are unlikely to be a foci of prion propagation in the brain. In contrast, neurons and astrocytes are known to be involved in prion replication and spread. Moreover, certain astrocytes, such as A1 reactive astrocytes, have proven neurotoxic in other neurodegenerative diseases, and thus might also influence the progression of prion-associated neurodegeneration.
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Cushman, M., B. S. Johnson, O. D. King, A. D. Gitler y J. Shorter. "Prion-like disorders: blurring the divide between transmissibility and infectivity". Journal of Cell Science 123, n.º 8 (31 de marzo de 2010): 1191–201. http://dx.doi.org/10.1242/jcs.051672.
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Hasegawa, Masato, Takashi Nonaka y Masami Masuda-Suzukake. "Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders". Pharmacology & Therapeutics 172 (abril de 2017): 22–33. http://dx.doi.org/10.1016/j.pharmthera.2016.11.010.
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