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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 ?-synuclein preformed fibrils.

ABSTRACT: Animal models that accurately recapitulate the accumulation of alpha-synuclein (?-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 ?-syn accumulation and nigrostriatal degeneration, and to understand the time course of both. Rats were injected unilaterally with different quantities of ?-syn PFFs (8 or 16??g of total protein) into striatal sites selected to concentrate ?-syn inclusion formation in the substantia nigra pars compacta (SNpc). Rats displayed an ?-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??g PFF injection also resulted in modest sensorimotor deficits in forelimb adjusting steps associated with degeneration at 6?months. Bilateral injection of 16??g ?-syn PFFs resulted in symmetric bilateral degeneration equivalent to the ipsilateral nigral degeneration observed following unilateral 16??g PFF injection (~50% loss). Bilateral PFF injections additionally resulted in alterations in several gait analysis parameters. These ?-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.

SUBMITTER: Patterson JR

PROVIDER: S-EPMC6701176 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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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.

Patterson Joseph R JR Duffy Megan F MF Kemp Christopher J CJ Howe Jacob W JW Collier Timothy J TJ Stoll Anna C AC Miller Kathryn M KM Patel Pooja P Levine Nathan N Moore Darren J DJ Luk Kelvin C KC Fleming Sheila M SM Kanaan Nicholas M NM Paumier Katrina L KL El-Agnaf Omar M A OMA Sortwell Caryl E CE

Neurobiology of disease 20190702

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 nig ...[more]

PMID: 31276792

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Project description:Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

Project description:IntroductionAccurate demonstration of phosphorylated α-synuclein aggregation and propagation, progressive nigrostriatal degeneration and motor deficits will help further research on elucidating the mechanisms of Parkinson's Disease. α-synucleinN103 and tauN368, cleaved by activated asparagine endopeptidase in Parkinson's Disease, robustly interacted with each other and triggered endogenous α-synuclein accumulation in a strong manner. However, the detailed pathophysiological process caused by the complex remains to be established.MethodsIn this study, rats were unilaterally inoculated with 15 or 30 μg of this complex or vehicle (phosphate buffered saline, PBS). Over a 6-month period post injection, we then investigated the abundance of pSyn inclusions, nigrostriatal degeneration, and changes in axonal transport proteins to identify the various dynamic pathological changes caused by pSyn aggregates in the nigrostriatal system.ResultsAs expected, rats displayed a dose-dependent increase in the amount of α-synuclein inclusions, and progressive dopaminergic neurodegeneration was observed throughout the study, reaching 30% at 6 months post injection. Impairments in anterograde axonal transport, followed by retrograde transport, were observed prior to neuron death, which was first discovered in the PFFs model.DiscussionThe current results demonstrate the value of a novel rat model of Parkinson's disease characterized by widespread, "seed"-initiated endogenous α-Syn pathology, impaired axonal transport, and a neurodegenerative cascade in the nigrostriatal system. Notably, the present study is the first to examine alterations in axonal transport proteins in a PFF model, providing an appropriate foundation for future research regarding the mechanisms leading to subsequent neurodegeneration. As this model recapitulates some essential features of Parkinson's disease, it provides an important platform for further research on specific pathogenic mechanisms and pre-clinical evaluations of novel therapeutic strategies.

Dataset Information

Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal ?-synuclein preformed fibrils.

Publications

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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