Mutability of prions

Li, Jiali; Mahal, Sukhvir P.; Demczyk, Cheryl A.; Weissmann, Charles

doi:10.1038/embor.2011.191

Cited by 31 publications

(39 citation statements)

References 21 publications

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“…In the experiments on the replication of 263K, HY, or SSLOW in dgPMCAb, we observed structural plasticity as reflected by the ability of the strains to change their PK resistance profile in response to different degrees of substrate glycosylation, while retaining molecular features responsible for the strain-specific phenotype. The concepts of phenotypic plasticity and norm of reaction can also be useful for explaining the reversible changes in strain characteristics upon altering the replication environment, for instance, when brain-derived prions are replicated in PMCA and then transferred back to animals (18,19,23) or replicated in cultured cells and then back into animals (2,5).…”

Section: Discussionmentioning

confidence: 99%

“…Should we attribute vast phenotypic variations, for example those observed in cell lines (2,5), to actual strain mutations or to phenotypic plasticity due to replication in altered cellular environments? Is the term mutation applicable when someone deals with reversible or interconvertible changes between quasispecies or substrains?…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that prion strains exist as a mixture of quasispecies; the populations of quasispecies are dynamic and can adapt quickly in response to changes in their replication environment (2,4). Changes in replication environment can be associated with prion transmission from animals to cultured cell lines and/or PMCA reactions and vice versa and associated with supplementing physiologically active compounds or drugs to cultured cells or PMCA reactions (2,(5)(6)(7).…”

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confidence: 99%

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Selective Amplification of Classical and Atypical Prions Using Modified Protein Misfolding Cyclic Amplification

Makarava

Savtchenko

Baskakov

2013

Journal of Biological Chemistry

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Background:The mechanisms of prion strain mutation and its dependence on the environment are not known. Results: Glycosylation status of PrP C substrate and cofactors controls the selectivity of amplification of classical and atypical PrP Sc . Conclusion: Amplification selectivity of alternative prion states can be regulated by modification of a substrate and cofactors in PMCA. Significance: Alternative prion states can be selectively amplified from a mixture.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Selective Amplification of Classical and Atypical Prions Using Modified Protein Misfolding Cyclic Amplification

Makarava

Savtchenko

Baskakov

2013

Journal of Biological Chemistry

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“…Importantly, complete genetic ablation of Tau is fairly well tolerated in mice, suggesting that anti-Tau antibodies in the adult CNS are unlikely to meet safety concerns due to disruption of normal Tau physiology (68 -70). Finally, if parallels to prion disease hold true, there could be variable clinical responses in patients based on the conformation of the pathogenic species, and possibly evolution of protein aggregate structures away from a given therapy (71,72). Although the most important criterion will be the efficacy of an antibody in vivo, a strong understanding of the biology of the most effective agents will enable better selection and optimization.…”

Section: Antibodies To Target Pathologymentioning

confidence: 99%

Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target

Holmes

Diamond

2014

Journal of Biological Chemistry

175

133

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Work over the past 4 years indicates that multiple proteins associated with neurodegenerative diseases, especially Tau and ␣-synuclein, can propagate aggregates between cells in a prionlike manner. This means that once an aggregate is formed it can escape the cell of origin, contact a connected cell, enter the cell, and induce further aggregation via templated conformational change. The prion model predicts a key role for extracellular protein aggregates in mediating progression of disease. This suggests new therapeutic approaches based on blocking neuronal uptake of protein aggregates and promoting their clearance. This will likely include therapeutic antibodies or small molecules, both of which can be developed and optimized in vitro prior to preclinical studies.Neurodegenerative diseases account for an enormous human and financial cost to our society, estimated in excess of $200 billion annually (1). Despite decades of study, there is no disease-modifying therapy. Virtually all neurodegenerative diseases are associated with the accumulation of fibrillar protein aggregates, and all are relentlessly progressive. There is now abundant evidence for an association of neuronal networks with patterns of spread through the brain (2-4). Studies of relatively rare, dominantly inherited neurodegenerative diseases have indicated that proteins that accumulate in sporadic forms of disease, such as prion protein, Tau, ␣-synuclein, and TDP-43, also cause pathology in the setting of destabilizing point mutations (5-8). This provides a strong indication that protein aggregation is itself a proximal cause of disease and is not simply an epiphenomenon. Indeed, protein aggregation is the most unifying pathological feature of adult onset neurodegenerative disorders. The proximal initiators of protein aggregation likely vary among different proteins and cell types, whereas the accumulation of misfolded species in general appears to be linked to the age-dependent breakdown of cellular quality control pathways (9, 10). It is not understood, however, why neurodegenerative diseases are relentlessly progressive or why they involve neural networks (3,11,12). A variety of studies are consistent with the idea that mechanisms similar to those of propagation of prion pathology could underlie disease progression. Prion protein (PrP c ) 2 is a normal cellular protein that can be converted to a disease-causing conformation (PrP Sc ) through interaction with a pathogenic prion protein "seed." The conversion mechanism is not fully understood, but involves templated conformational change, whereby a PrP Sc seed contacts natively folded protein and induces it to assemble onto a growing aggregate. PrP Sc aggregates can have multiple conformations, each linked to unique pathological patterns (13-15), and they have been demonstrated in experimental systems to propagate through neural networks (16). Thus, the prion hypothesis provides a useful model by which to test ideas about propagation of protein pathology in other neurodegenerative diseases. Prion-...

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“…Thus, when 22L prions were transferred from brain to PK1 cells, they gradually changed their properties, losing their ability to infect R33 cells and becoming sensitive to inhibition by swainsonine; these changes were reversed when the prions were returned to brain (15,16,18). We believe that prion populations are quasispecies (9, 10), consisting of a multitude of variants, the ones fittest for a particular environment predominating (4,15,21), and we have shown that variants arise in cloned prion populations in the course of propagation (15,16,18), explaining how quasispecies arise.…”

Section: Discussionmentioning

confidence: 99%

The Extended Cell Panel Assay Characterizes the Relationship of Prion Strains RML, 79A, and 139A and Reveals Conversion of 139A to 79A-Like Prions in Cell Culture

Oelschlegel

Fallahi

Ortiz-Umpierre³

et al. 2012

J Virol

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Three commonly used isolates of murine prions, 79A, 139A, and RML, were derived from the so-called Chandler isolate, which was obtained by propagating prions from scrapie-infected goat brain in mice. RML is widely believed to be identical with 139A; however, using the extended cell panel assay (ECPA), we here show that 139A and RML isolates are distinct, while 79A and RML could not be distinguished. We undertook to clone 79A and 139A prions by endpoint dilution in murine neuroblastoma-derived PK1 cells. Cloned 79A prions, when returned to mouse brain, were unchanged and indistinguishable from RML by ECPA. However, 139A-derived clones, when returned to brain, yielded prions distinct from 139A and similar to 79A and RML. Thus, when 139A prions were transferred to PK1 cells, 79A/RML-like prions, either present as a minor component in the brain 139A population or generated by mutation in the cells, were selected and, after being returned to brain, were the major if not only component of the population.

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Mutability of prions

Abstract: Mutability of prionsPrions are shown to be mutable, and prion substrains have distinct mutation capacity. However, even clones that seem virtually immutable change when the environmental conditions are altered. Mutability is thus a prion substrain-specific attribute.

Cited by 31 publications

References 21 publications

Selective Amplification of Classical and Atypical Prions Using Modified Protein Misfolding Cyclic Amplification

Selective Amplification of Classical and Atypical Prions Using Modified Protein Misfolding Cyclic Amplification

Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target

The Extended Cell Panel Assay Characterizes the Relationship of Prion Strains RML, 79A, and 139A and Reveals Conversion of 139A to 79A-Like Prions in Cell Culture

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