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<a href="http://doi.org/10.1016/j.nbd.2019.104525" target="_blank" rel="noreferrer noopener">http://doi.org/10.1016/j.nbd.2019.104525</a>
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Pages
104525-104525
Volume
130
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Title
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Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrils
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Neurobiology of Disease
Date
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2019
2019-10
Subject
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Alpha-Synuclein; PARKINSON'S disease; Preformed fibrils; Synucleinopathy
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Patterson Joseph R; Duffy Megan F; Kemp Christopher J; Howe Jacob W; Collier Timothy J; Stoll Anna C; Miller Kathryn M; Patel Pooja; Levine Nathan; Moore Darren J; Luk Kelvin C; Fleming Sheila M; Kanaan Nicholas M; Paumier Katrina L; El-Agnaf Omar M A; Sortwell Caryl E
Description
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Animal models that accurately recapitulate the accumulation of alpha-synuclein (α-syn) inclusions, progressive neurodegeneration of the nigrostriatal system and motor deficits can be useful tools for Parkinson's disease (PD) research. The preformed fibril (PFF) synucleinopathy model in rodents generally displays these PD-relevant features, however, the magnitude and predictability of these events is far from established. We therefore sought to optimize the magnitude of α-syn accumulation and nigrostriatal degeneration, and to understand the time course of both. Rats were injected unilaterally with different quantities of α-syn PFFs (8 or 16 μg of total protein) into striatal sites selected to concentrate α-syn inclusion formation in the substantia nigra pars compacta (SNpc). Rats displayed an α-syn PFF quantity-dependent increase in the magnitude of ipsilateral SNpc inclusion formation at 2 months and bilateral loss of nigral dopamine neurons at 6 months. Unilateral 16 μg PFF injection also resulted in modest sensorimotor deficits in forelimb adjusting steps associated with degeneration at 6 months. Bilateral injection of 16 μg α-syn PFFs resulted in symmetric bilateral degeneration equivalent to the ipsilateral nigral degeneration observed following unilateral 16 μg PFF injection (~50% loss). Bilateral PFF injections additionally resulted in alterations in several gait analysis parameters. These α-syn PFF parameters can be applied to generate a reproducible synucleinopathy model in rats with which to study pathogenic mechanisms and vet potential disease-modifying therapies.
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<a href="http://doi.org/10.1016/j.nbd.2019.104525" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2019.104525</a>
2019
Alpha-synuclein
Collier Timothy J
Department of Family & Community Medicine
Department of Pharmaceutical Sciences
Duffy Megan F
El-Agnaf Omar M A
Fleming Sheila M
Howe Jacob W
Kanaan Nicholas M
Kemp Christopher J
Levine Nathan
Luk Kelvin C
Miller Kathryn M
Moore Darren J
NEOMED College of Medicine
NEOMED College of Pharmacy
Neurobiology of disease
Parkinson's disease
Patel Pooja
Patterson Joseph R
Paumier Katrina L
Preformed fibrils
September 2019 Update
Sortwell Caryl E
Stoll Anna C
Synucleinopathy