Objective: Optimization of the surgical parameters (intrastriatal placement and concentration of alpha-synuclein preformed fibrils; α-syn PFFs) to increase the magnitude of nigrostriatal α-syn pathology and resultant degeneration.

Background: Existing models of Parkinson’s disease (PD) have been unable to predict clinical translation. Specifically, no animal model of PD has simultaneously incorporated widespread α – α-syn pathology, protracted and significant nigrostriatal degeneration and consistent motor impairments. Previously, we demonstrated that injection of mouse α-syn PFFs unilaterally into rats results in significant accumulation of α-syn pathology and bilateral nigrostriatal degeneration (≈ 40% loss, Paumier et al., 2015). However, the nigrostriatal degeneration was not of sufficient magnitude to produce consistent motor deficits. In the present study we analyzed whether more precisely targeting the nigrostriatal terminal field within the dorsal striatum and increasing the amount of mouse α-syn PFFs could augment synucleinopathy, loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc) and produce motor impairments.

Methods: Male Fischer 344 rats (n=88) were injected with 8 µg α-syn PFFs, 16 µg α-syn PFFs, 16 µg α-syn monomer or an equal volume of vehicle in two sites of the dorsal striatum. Post-mortem pathology was evaluated at 2, 4, and 6 months after surgery. Unbiased stereological assessment was used to quantify tyrosine hydroxylase immunoreactive, total neurons and phosphorylated α-syn (pSer129) in the SNpc. Motor performance of the 6 month cohort was assessed to examine forelimb use in the cylinder and adjusting steps task as well as locomotor activity in the open field and modified cylinder.

Results: Targeting of α-syn PFF placement to the dorsal striatum significantly concentrated α-syn pathology to the SNpc and decreased syn pathology in the ventral tegmental area (VTA). Stereological and behavioral analyses are ongoing and will be presented at the meeting.

Conclusions: Optimization of α-syn PFF-induced synucleinopathy in rats will leverage the distinct advantages of the rat model system compared to mice, i.e. more complex motor behaviors, greater synaptic complexity and sampling capability. Once successfully optimized, the α-syn rat PFF PD model will facilitate preclinical assessment of novel disease-modifying therapies for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/optimization-of-synucleinopathy-and-nigrostriatal-degeneration-induced-by-injection-of-alpha-synuclein-preformed-fibrils-into-rat-striatum/