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40
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Text
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<a href="http://doi.org/10.1074/jbc.RA119.007743" target="_blank" rel="noreferrer noopener">http://doi.org/10.1074/jbc.RA119.007743</a>
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Title
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Defining α-synuclein species responsible for Parkinson disease phenotypes in mice
Publisher
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The Journal of Biological Chemistry
Date
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2019
2019-05
Subject
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alpha-synuclein (a-synuclein); amyloid; cytotoxicity; fibril; Lewy Body; motor behavior defect; neurodegenerative disease; oligomer; Parkinson disease; protein aggregation
Creator
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Froula Jessica M; Castellana-Cruz Marta; Anabtawi Nadia M; Camino José D; Chen Serene W; Thrasher Drake R; Freire Jennifer; Yazdi Allen A; Fleming Sheila; Dobson Christopher M; Kumita Janet R; Cremades Nunilo; Volpicelli-Daley Laura A
Description
An account of the resource
Parkinson disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregated α-synuclein. These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions in order to halt disease progression. α-Synuclein exists in multiple structural forms, including disordered, non-amyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable amyloid β-sheet oligomers compared with those of fibrillar α-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different α-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found that β-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small β-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor behavior defects. We conclude that although the β-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric α-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation of β-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders.
Identifier
An unambiguous reference to the resource within a given context
<a href="http://doi.org/10.1074/jbc.RA119.007743" target="_blank" rel="noreferrer noopener">10.1074/jbc.RA119.007743</a>
2019
alpha-synuclein (a-synuclein)
amyloid
Anabtawi Nadia M
Camino José D
Castellana-Cruz Marta
Chen Serene W
Cremades Nunilo
cytotoxicity
Department of Pharmaceutical Sciences
Dobson Christopher M
fibril
Fleming Sheila
Freire Jennifer
Froula Jessica M
June 2019 Update
Kumita Janet R
Lewy Body
motor behavior defect
NEOMED College of Pharmacy
neurodegenerative disease
oligomer
Parkinson Disease
Protein Aggregation
The Journal of biological chemistry
Thrasher Drake R
Volpicelli-Daley Laura A
Yazdi Allen A
-
Text
A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text.
URL Address
<a href="http://doi.org/10.1074/jbc.ra119.007743" target="_blank" rel="noreferrer noopener">http://doi.org/10.1074/jbc.ra119.007743</a>
Rights
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Pages
10392-10406
Issue
27
Volume
294
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Dublin Core
The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.
Title
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Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice.
Publisher
An entity responsible for making the resource available
Journal of Biological Chemistry
Date
A point or period of time associated with an event in the lifecycle of the resource
2019
2019-07
Subject
The topic of the resource
DOPAMINERGIC neurons; FOURIER transform infrared spectroscopy; MOUSE diseases; PARKINSON'S disease; SPECIES; SUBSTANTIA nigra
Creator
An entity primarily responsible for making the resource
Froula Jessica M; Castellana-Cruz Marta; Anabtawi Nadia M; Camino José D; Chen Serene W; Thrasher Drake R; Freire Jennifer; Yazdi Allen A; Fleming Sheila; Dobson Christopher M; Kumita Janet R; Cremades Nunilo; Volpicelli-Daley Laura A
Description
An account of the resource
Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregatedβ-synuclein (β-syn). These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions to halt disease progression. β-Synuclein exists in multiple structural forms, including disordered, nonamyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable α-amyloid-sheet oligomers compared with those of fibrillar β-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different β-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found thatα-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small α-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor-behavior defects. We conclude that although theα-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric β-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation ofα-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders. [ABSTRACT FROM AUTHOR]
Identifier
An unambiguous reference to the resource within a given context
<a href="http://doi.org/10.1074/jbc.ra119.007743" target="_blank" rel="noreferrer noopener">10.1074/jbc.ra119.007743</a>
2019
Anabtawi Nadia M
Camino José D
Castellana-Cruz Marta
Chen Serene W
Cremades Nunilo
Department of Pharmaceutical Sciences
Dobson Christopher M
DOPAMINERGIC neurons
Fleming Sheila
FOURIER transform infrared spectroscopy
Freire Jennifer
Froula Jessica M
Journal of Biological Chemistry
Kumita Janet R
MOUSE diseases
NEOMED College of Pharmacy
Parkinson's disease
September 2019 Update
SPECIES
SUBSTANTIA nigra
Thrasher Drake R
Volpicelli-Daley Laura A
Yazdi Allen A