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Article ; Online: Biology and genetics of prions causing neurodegeneration.

Prusiner, Stanley B

2013 Volume 47, Page(s) 601–623

Abstract: Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are ... ...

Abstract	Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.
MeSH term(s)	Age of Onset ; Amyloidogenic Proteins/chemistry ; Amyloidogenic Proteins/classification ; Amyloidogenic Proteins/physiology ; Animals ; Fungal Proteins/chemistry ; Fungal Proteins/classification ; Fungal Proteins/physiology ; Humans ; Inclusion Bodies ; Mammals ; Models, Molecular ; Neurodegenerative Diseases/epidemiology ; Neurodegenerative Diseases/etiology ; Neurodegenerative Diseases/genetics ; Neurofibrillary Tangles ; Peptide Termination Factors/chemistry ; Peptide Termination Factors/classification ; Peptide Termination Factors/physiology ; Plaque, Amyloid ; Prion Diseases/etiology ; Prion Diseases/genetics ; Prions/genetics ; Prions/physiology ; Protein Conformation ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/classification ; Saccharomyces cerevisiae Proteins/physiology ; Synucleins/physiology ; Tauopathies/etiology ; Tauopathies/genetics ; Transcription Factors/chemistry ; Transcription Factors/classification ; Virulence ; mRNA Cleavage and Polyadenylation Factors/chemistry ; mRNA Cleavage and Polyadenylation Factors/classification ; tau Proteins/genetics ; tau Proteins/physiology
Chemical Substances	Amyloidogenic Proteins ; CPEB1 protein, human ; Fungal Proteins ; HET-S protein, Podospora anserina ; Peptide Termination Factors ; Prions ; SUP35 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins ; Synucleins ; Transcription Factors ; mRNA Cleavage and Polyadenylation Factors ; tau Proteins
Language	English
Publishing date	2013-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	207928-8
ISSN	1545-2948 ; 0066-4170 ; 0066-4197
ISSN (online)	1545-2948
ISSN	0066-4170 ; 0066-4197
DOI	10.1146/annurev-genet-110711-155524
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Article ; Online: How an Infection of Sheep Revealed Prion Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders

George A. Carlson / Stanley B. Prusiner

International Journal of Molecular Sciences, Vol 22, Iss 4861, p

2021 Volume 4861

Abstract: ... disorders, there is little disagreement that Alzheimer’s disease (AD), Parkinson’s ...

Abstract	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.
Keywords	Aβ ; α-synuclein ; Alzheimer’s disease ; neurodegenerative disease ; prions ; PrP ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	630
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human α-synuclein.

Krejciova, Zuzana / Carlson, George A / Giles, Kurt / Prusiner, Stanley B

Acta neuropathologica communications

2019 Volume 7, Issue 1, Page(s) 81

Abstract: ... inclusions in synucleinopathies: hyperphosphorylation preceded by aggregation, ubiquitination, thioflavin S ...

Abstract	Glial cytoplasmic inclusions (GCIs) containing aggregated and hyperphosphorylated α-synuclein are the signature neuropathological hallmark of multiple system atrophy (MSA). Native α-synuclein can adopt a prion conformation that self-propagates and spreads throughout the brain ultimately resulting in neurodegeneration. A growing body of evidence argues that, in addition to oligodendrocytes, astrocytes contain α-synuclein inclusions in MSA and other α-synucleinopathies at advanced stages of disease. To study the role of astrocytes in MSA, we added MSA brain homogenate to primary cultures of astrocytes from transgenic (Tg) mouse lines expressing human α-synuclein. Astrocytes from four Tg lines, expressing either wild-type or mutant (A53T or A30P) human α-synuclein, propagated and accumulated α-synuclein prions. Furthermore, we found that MSA-infected astrocytes formed two morphologically distinct α-synuclein inclusions: filamentous and granular. Both types of cytoplasmic inclusions shared several features characteristic of α-synuclein inclusions in synucleinopathies: hyperphosphorylation preceded by aggregation, ubiquitination, thioflavin S-positivity, and co-localization with p62. Our findings demonstrate that human α-synuclein forms distinct inclusion morphologies and propagates within cultured Tg astrocytes exposed to MSA prions, indicating that α-synuclein expression determines the tropism of inclusion formation in certain cells. Thus, our work may prove useful in elucidating the role of astrocytes in the pathogenic mechanisms that feature in neurodegeneration caused by MSA prions.
MeSH term(s)	Animals ; Astrocytes/metabolism ; Astrocytes/pathology ; Cells, Cultured ; Dendritic Spines/metabolism ; Dendritic Spines/pathology ; Humans ; Inclusion Bodies/metabolism ; Inclusion Bodies/pathology ; Mice, Transgenic ; Multiple System Atrophy/metabolism ; Multiple System Atrophy/pathology ; Prions/metabolism ; Recombinant Proteins/administration & dosage ; alpha-Synuclein/administration & dosage ; alpha-Synuclein/metabolism
Chemical Substances	Prions ; Recombinant Proteins ; alpha-Synuclein
Language	English
Publishing date	2019-05-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-019-0703-9
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Article ; Online: Water-Soluble Iridium Photoredox Catalyst for the Trifluoromethylation of Biomolecule Substrates in Phosphate Buffered Saline Solvent.

Nguyen, Terrence-Thang H / O'Brien, Connor J / Tran, Minh L N / Olson, Steven H / Settineri, Nicholas S / Prusiner, Stanley B / Paras, Nick A / Conrad, Jay

Organic letters

2021 Volume 23, Issue 10, Page(s) 3823–3827

Abstract: The development of a water-soluble iridium catalyst enables the trifluoromethylation of polar small molecules and peptides in DMSO solution or aqueous media. The reaction was optimized in a microtiter plate format under ambient air, using commercial ... ...

Abstract	The development of a water-soluble iridium catalyst enables the trifluoromethylation of polar small molecules and peptides in DMSO solution or aqueous media. The reaction was optimized in a microtiter plate format under ambient air, using commercial Langlois reagent as a CF
MeSH term(s)	Catalysis ; Hydrocarbons, Fluorinated/chemistry ; Iridium/chemistry ; Light ; Mesylates/chemistry ; Molecular Structure ; Phosphates/chemistry ; Solvents ; Water
Chemical Substances	Hydrocarbons, Fluorinated ; Mesylates ; Phosphates ; Solvents ; sodium trifluoromethanesulfinate ; Water (059QF0KO0R) ; Iridium (44448S9773)
Language	English
Publishing date	2021-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1523-7052
ISSN (online)	1523-7052
DOI	10.1021/acs.orglett.1c00871
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Article ; Online: Trans-channel fluorescence learning improves high-content screening for Alzheimer's disease therapeutics.

Wong, Daniel R / Conrad, Jay / Johnson, Noah / Ayers, Jacob / Laeremans, Annelies / Lee, Joanne C / Lee, Jisoo / Prusiner, Stanley B / Bandyopadhyay, Sourav / Butte, Atul J / Paras, Nick A / Keiser, Michael J

Nature machine intelligence

2022 Volume 4, Issue 6, Page(s) 583–595

Abstract: In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations, such as the labor and preparation formats needed to produce different image ... ...

Abstract	In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations, such as the labor and preparation formats needed to produce different image channels, hinders the use of certain fluorescent markers. Consequently, completed screens may lack biologically informative but experimentally impractical markers. Here, we present a deep learning method for overcoming these limitations. We accurately generated predicted fluorescent signals from other related markers and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of biologically active compounds for Alzheimer's disease (AD) from a completed high-content high-throughput screen (HCS) that had only contained the original markers. The ML method identified novel compounds that effectively blocked tau aggregation, which had been missed by traditional screening approaches unguided by ML. The method improved triaging efficiency of compound rankings over conventional rankings by raw image channels. We reproduced this ML pipeline on a biologically independent cancer-based dataset, demonstrating its generalizability. The approach is disease-agnostic and applicable across diverse fluorescence microscopy datasets.
Language	English
Publishing date	2022-05-30
Publishing country	England
Document type	Journal Article
ISSN	2522-5839
ISSN (online)	2522-5839
DOI	10.1038/s42256-022-00490-8
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Article ; Online: Kinetics of α-synuclein prions preceding neuropathological inclusions in multiple system atrophy.

Woerman, Amanda L / Patel, Smita / Kazmi, Sabeen A / Oehler, Abby / Lee, Jisoo / Mordes, Daniel A / Olson, Steven H / Prusiner, Stanley B

PLoS pathogens

2020 Volume 16, Issue 2, Page(s) e1008222

Abstract: Multiple system atrophy (MSA), a progressive neurodegenerative disease characterized by autonomic dysfunction and motor impairment, is caused by the self-templated misfolding of the protein α-synuclein. With no treatment currently available, we sought to ...

Abstract	Multiple system atrophy (MSA), a progressive neurodegenerative disease characterized by autonomic dysfunction and motor impairment, is caused by the self-templated misfolding of the protein α-synuclein. With no treatment currently available, we sought to characterize the spread of α-synuclein in a transgenic mouse model of MSA prion propagation to support drug discovery programs for synucleinopathies. Brain homogenates from MSA patient samples or mouse-passaged MSA were inoculated either by standard freehand injection or stereotactically into TgM83+/- mice, which express human α-synuclein with the A53T mutation. Following disease onset, brains from the mice were tested for biologically active α-synuclein prions using a cell-based assay and examined for α-synuclein neuropathology. Inoculation studies using homogenates prepared from brain regions lacking detectable α-synuclein neuropathology transmitted neurological disease to mice. Terminal animals contained similar concentrations of α-synuclein prions; however, a time-course study where mice were terminated every five days through disease progression revealed that the kinetics of α-synuclein prion replication in the mice were variable. Stereotactic inoculation into the thalamus reduced variability in disease onset in the mice, although incubation times were consistent with standard inoculations. Using human samples with and without neuropathological lesions, we observed that α-synuclein prion formation precedes neuropathology in the brain, suggesting that disease in patients is not limited to brain regions containing neuropathological lesions.
MeSH term(s)	Animals ; Brain/metabolism ; Brain/pathology ; Female ; Humans ; Kinetics ; Male ; Mice ; Mice, Transgenic ; Multiple System Atrophy/genetics ; Multiple System Atrophy/metabolism ; Multiple System Atrophy/pathology ; Point Mutation ; Prions/genetics ; Prions/metabolism ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
Chemical Substances	Prions ; SNCA protein, human ; Snca protein, mouse ; alpha-Synuclein
Language	English
Publishing date	2020-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1008222
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Article: Shattuck lecture--neurodegenerative diseases and prions.

Prusiner, S B

The New England journal of medicine

2001 Volume 344, Issue 20, Page(s) 1516–1526

MeSH term(s)	Age Factors ; Diagnosis, Differential ; Neurodegenerative Diseases/diagnosis ; Neurodegenerative Diseases/epidemiology ; Neurodegenerative Diseases/therapy ; Prion Diseases/diagnosis ; Prion Diseases/epidemiology ; Prion Diseases/prevention & control ; Prion Diseases/transmission ; Prions/chemistry ; Prions/classification ; Prions/pathogenicity
Chemical Substances	Prions
Language	English
Publishing date	2001-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJM200105173442006
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Article: Water-Soluble Iridium Photoredox Catalyst for the Trifluoromethylation of Biomolecule Substrates in Phosphate Buffered Saline Solvent

Nguyen, Terrence-Thang H / O’Brien, Connor J / Tran, Minh L. N / Olson, Steven H / Settineri, Nicholas S / Prusiner, Stanley B / Paras, Nick A / Conrad, Jay

Organic letters. 2021 Apr. 30, v. 23, no. 10

2021

Abstract	The development of a water-soluble iridium catalyst enables the trifluoromethylation of polar small molecules and peptides in DMSO solution or aqueous media. The reaction was optimized in a microtiter plate format under ambient air, using commercial Langlois reagent as a CF₃ radical source, blue LEDs for excitation, and using DPBS as solvent to provide up to 60% CF₃– peptide.
Keywords	air ; catalysts ; iridium ; peptides ; phosphates ; redox reactions ; solvents ; water solubility
Language	English
Dates of publication	2021-0430
Size	p. 3823-3827.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-AP-2-clean
ISSN	1523-7052
DOI	10.1021/acs.orglett.1c00871
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments

Gregory E. Merz / Matthew J. Chalkley / Sophia K. Tan / Eric Tse / Joanne Lee / Stanley B. Prusiner / Nick A. Paras / William F. DeGrado / Daniel R. Southworth

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 11

Abstract: ... hallmark of Alzheimer’s disease (AD) and many other neurodegenerative tauopathies. The filaments adopt ...

Abstract	Abstract Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer’s disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo–electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule–protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.
Keywords	Science ; Q
Subject code	612
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The prion diseases.

Prusiner, S B

Brain pathology (Zurich, Switzerland)

1998 Volume 8, Issue 3, Page(s) 499–513

Abstract: The human prion diseases are fatal neurodegenerative maladies that may present as sporadic, genetic, or infectious illnesses. The sporadic form is called Creutzfeldt-Jakob disease (CJD) while the inherited disorders are called familial (f) CJD, Gerstmann- ...

Abstract	The human prion diseases are fatal neurodegenerative maladies that may present as sporadic, genetic, or infectious illnesses. The sporadic form is called Creutzfeldt-Jakob disease (CJD) while the inherited disorders are called familial (f) CJD, Gerstmann-Straussler-Scheinker (GSS) disease and fatal familial insomnia (FFI). Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular PrP (PrPC) is converted into PrPSc through a posttranslational process during which it acquires a high beta-sheet content. In fCJD, GSS, and FFI, mutations in the PrP gene located on the short arm of chromosome 20 are the cause of disease. Considerable evidence argues that the prion diseases are disorders of protein conformation.
MeSH term(s)	Animals ; Creutzfeldt-Jakob Syndrome/prevention & control ; Creutzfeldt-Jakob Syndrome/therapy ; Creutzfeldt-Jakob Syndrome/transmission ; Encephalopathy, Bovine Spongiform/epidemiology ; Humans ; Models, Molecular ; Prion Diseases/diagnosis ; Prion Diseases/etiology ; Prion Diseases/genetics ; Prion Diseases/transmission ; Prions/chemistry ; Prions/pathogenicity ; Scrapie/prevention & control ; Scrapie/therapy ; Scrapie/transmission
Chemical Substances	Prions
Language	English
Publishing date	1998-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
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Zs.A 3585: Show issues

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