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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
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The Journal of Biological Chemistry
Date
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2019
2019-05
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alpha-synuclein (a-synuclein); amyloid; cytotoxicity; fibril; Lewy Body; motor behavior defect; neurodegenerative disease; oligomer; Parkinson disease; protein aggregation
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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
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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.
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<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