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.

Autor: Patterson JR; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA. Electronic address: Joseph.Patterson@hc.msu.edu., Duffy MF; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA., Kemp CJ; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA., Howe JW; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA., Collier TJ; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA., Stoll AC; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA., Miller KM; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA., Patel P; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA., Levine N; Center of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA., Moore DJ; Center of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA., Luk KC; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Fleming SM; College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, USA., Kanaan NM; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA., Paumier KL; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA., El-Agnaf OMA; Neurological Disorders Researcher Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar., Sortwell CE; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2019 Oct; Vol. 130, pp. 104525. Date of Electronic Publication: 2019 Jul 02.
DOI: 10.1016/j.nbd.2019.104525
Abstrakt: 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.
(Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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