Objective: Generation of a synucleinopathy model in rats using injections of α-synuclein preformed fibrils (α-syn PFFs) resulting in robust and widespread α-syn pathology and at least 50% nigrostriatal degeneration.

Background: Genetic, viral vector, and neurotoxicant models of Parkinson’s disease (PD) fail to recapitulate all the key features of PD. We have previously demonstrated that intrastriatal injections of sonicated α-syn PFFs result in widespread α-syn pathology and progressive bilateral nigrostriatal degeneration (≈30-40%) in rats. This degree of degeneration was not sufficient to produce motor deficits. The present study utilizes optimized stereotaxic coordinates in the dorsal striatum and an increased concentration of α-syn PFFs in attempt to increase the magnitude of nigral α-syn pathology, neurodegeneration, and elicit motor deficits.

Methods: Male Fischer 344 rats (n=88) were injected with 8 or 16 total μg of α-syn PFFs, 16 μg α-syn monomer or an equal volume of vehicle at two sites of the dorsal striatum. Post-mortem pathology and motor performance was evaluated at 2, 4, and 6 months after surgery.

Results: At 2-months post-injection (p.i.), the peak of phosphorylated α-syn inclusions was observed in the SNpc with approximately 35% of nigral dopamine neurons accumulating phosphorylated α-syn. Increased amounts of α-syn PFF concentration resulted in significant bilateral nigrostriatal degeneration with substantia nigra pars compacta (SNpc) loss as high as ~59% ipsilateral and ~55% contralateral to injection at the 6-months p.i. Ipsilateral degeneration preceded contralateral degeneration, with significant degeneration of 35% of the ipsilateral SNpc neurons observed at 4 months compared to only 4% loss contralaterally at this same time point. Rats receiving the highest concentration of α-syn PFFs exhibited significant contralateral forelimb akinesia (~20% reduction, p = 0.0254) as assessed via the adjusting steps task.

Conclusions: Increased amounts of α-syn PFFs and optimized striatal injection coordinates can exacerbate the magnitude of synucleinopathy and nigrostriatal degeneration in rats, resulting in significant motor impairments. The α-syn PFF rat synucleinopathy model can serve as a valuable platform for allowing new therapies to be tested in a preclinical model of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pronounced-synucleinopathy-and-nigrostriatal-degeneration-result-in-forelimb-use-deficits-in-the-rat-preformed-alpha-synuclein-fibril-model/