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, P. Patel, Nathan Levine, Darren J. Moore, Kelvin C. Luk, Sheila M. Fleming, Nicholas M. Kanaan, Katrina L. Paumier, Omar Ali El-Agnaf, Caryl E. Sortwell

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number104525
JournalNeurobiology of Disease
Volume130
DOIs
Publication statusPublished - 1 Oct 2019

Fingerprint

Synucleins
alpha-Synuclein
Injections
Substantia Nigra
Parkinson Disease
Corpus Striatum
Forelimb
Dopaminergic Neurons
Gait
Rodentia
Animal Models
Research
Proteins

Keywords

  • Alpha-Synuclein
  • Parkinson's disease
  • Preformed fibrils
  • Synucleinopathy

ASJC Scopus subject areas

  • Neurology

Cite this

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. / Patterson, Joseph R.; Duffy, Megan F.; Kemp, Christopher J.; Howe, Jacob W.; Collier, Timothy J.; Stoll, Anna C.; Miller, Kathryn M.; Patel, P.; Levine, Nathan; Moore, Darren J.; Luk, Kelvin C.; Fleming, Sheila M.; Kanaan, Nicholas M.; Paumier, Katrina L.; Ali El-Agnaf, Omar; Sortwell, Caryl E.

In: Neurobiology of Disease, Vol. 130, 104525, 01.10.2019.

Research output: Contribution to journalArticle

Patterson, JR, Duffy, MF, Kemp, CJ, Howe, JW, Collier, TJ, Stoll, AC, Miller, KM, Patel, P, Levine, N, Moore, DJ, Luk, KC, Fleming, SM, Kanaan, NM, Paumier, KL, Ali El-Agnaf, O & Sortwell, CE 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', Neurobiology of Disease, vol. 130, 104525. https://doi.org/10.1016/j.nbd.2019.104525
Patterson, Joseph R. ; Duffy, Megan F. ; Kemp, Christopher J. ; Howe, Jacob W. ; Collier, Timothy J. ; Stoll, Anna C. ; Miller, Kathryn M. ; Patel, P. ; Levine, Nathan ; Moore, Darren J. ; Luk, Kelvin C. ; Fleming, Sheila M. ; Kanaan, Nicholas M. ; Paumier, Katrina L. ; Ali El-Agnaf, Omar ; Sortwell, Caryl E. / 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. In: Neurobiology of Disease. 2019 ; Vol. 130.
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abstract = "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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AU - Duffy, Megan F.

AU - Kemp, Christopher J.

AU - Howe, Jacob W.

AU - Collier, Timothy J.

AU - Stoll, Anna C.

AU - Miller, Kathryn M.

AU - Patel, P.

AU - Levine, Nathan

AU - Moore, Darren J.

AU - Luk, Kelvin C.

AU - Fleming, Sheila M.

AU - Kanaan, Nicholas M.

AU - Paumier, Katrina L.

AU - Ali El-Agnaf, Omar

AU - Sortwell, Caryl E.

PY - 2019/10/1

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N2 - 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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