• Neurobiology of disease · Oct 2019

    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.

    • Joseph R Patterson, Megan F Duffy, Christopher J Kemp, Jacob W Howe, Timothy J Collier, Anna C Stoll, Kathryn M Miller, Pooja Patel, Nathan Levine, Darren J Moore, Kelvin C Luk, Sheila M Fleming, Nicholas M Kanaan, Katrina L Paumier, El-AgnafOmar M AOMANeurological Disorders Researcher Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar., and Caryl E Sortwell.
    • Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA. Electronic address: Joseph.Patterson@hc.msu.edu.
    • Neurobiol. Dis. 2019 Oct 1; 130: 104525.

    AbstractAnimal 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.

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