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
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...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-10-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119301937 |
| _version_ | 1824022783950061568 |
|---|---|
| author | 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 Omar M.A. El-Agnaf Caryl E. Sortwell |
| author_facet | 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 Omar M.A. El-Agnaf Caryl E. Sortwell |
| author_sort | Joseph R. Patterson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T09:25:44Z |
| format | Article |
| id | doaj.art-758f84c3154542e3af56b5659a3f143d |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-19T09:25:44Z |
| publishDate | 2019-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-758f84c3154542e3af56b5659a3f143d2022-12-21T20:27:49ZengElsevierNeurobiology of Disease1095-953X2019-10-01130104525Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrilsJoseph R. Patterson0Megan F. Duffy1Christopher J. Kemp2Jacob W. Howe3Timothy J. Collier4Anna C. Stoll5Kathryn M. Miller6Pooja Patel7Nathan Levine8Darren J. Moore9Kelvin C. Luk10Sheila M. Fleming11Nicholas M. Kanaan12Katrina L. Paumier13Omar M.A. El-Agnaf14Caryl E. Sortwell15Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Corresponding author.Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USADepartment of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USADepartment of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USADepartment 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, USADepartment of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USADepartment of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USADepartment of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USACenter of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USACenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USACollege of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, USADepartment 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, USADepartment of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USANeurological Disorders Researcher Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, QatarDepartment 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, USAAnimal 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.http://www.sciencedirect.com/science/article/pii/S0969996119301937Alpha-SynucleinPreformed fibrilsSynucleinopathyParkinson's disease |
| spellingShingle | 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 Omar M.A. El-Agnaf Caryl E. Sortwell 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 Neurobiology of Disease Alpha-Synuclein Preformed fibrils Synucleinopathy Parkinson's disease |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Alpha-Synuclein Preformed fibrils Synucleinopathy Parkinson's disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119301937 |
| work_keys_str_mv | AT josephrpatterson timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT meganfduffy timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT christopherjkemp timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT jacobwhowe timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT timothyjcollier timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT annacstoll timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT kathrynmmiller timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT poojapatel timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT nathanlevine timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT darrenjmoore timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT kelvincluk timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT sheilamfleming timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT nicholasmkanaan timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT katrinalpaumier timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT omarmaelagnaf timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils AT carylesortwell timecourseandmagnitudeofalphasynucleininclusionformationandnigrostriataldegenerationintheratmodelofsynucleinopathytriggeredbyintrastriatalasynucleinpreformedfibrils |