Objective: To develop a physiologically relevant model of PD.

Background: Intracerebral injection of pre-formed α-synuclein fibrils has emerged as an interesting tool to induce PD-like pathology and behavioral deficits in rodents. However, these changes are slow to develop taking six months or longer to appear.

Methods: Female SD rats were divided into 2 groups: one receiving AAV6-α-synuclein in substantia nigra (SN), 4 weeks prior to an injection of fibrils in the same site; the other receiving fibrils alone.

Results: With combined injection, a profound loss (55%) of TH positive cells in SN was observed already within 3 weeks of fibril injection, increasing to 65% at 24-weeks post fibril injection, while the striatal TH fiber density decreased from 70% by 3 weeks to 40% by 24 weeks. Injection of fibrils alone caused only a 30% cell loss in SN by 3 weeks, which increased to 55% by 24 weeks. Striatal TH fiber density decreased from 80% by 3 weeks to 60% by 24 weeks. In addition, a clear increase in the appearance of phosphorylated α-synuclein (p-syn) aggregates was observed in the combined group. While the p-syn puncta were visible in the nigral cells injected with fibrils alone, combination of fibrils and AAV-α-syn injection led to a much more extensive development of p-syn pathology. Further, there was an increase in the number and size of axonal swellings in striatum with combined injection regimen as compared to fibrils alone. While no behavioral deficits were observed in the fibril alone group, the combination group started to show a significant decline in contralateral paw use, as indicated by cylinder and stepping test, around 9 weeks that remained constant until 24 weeks.

Conclusions: The results indicate that the speed and severity of pathological changes induced by fibrils is greatly enhanced in the presence of elevated levels α-synuclein. They also suggest that the ability of exogenous fibrils to cause seeding and aggregation of α-synuclein is accelerated in α-synuclein overexpressing dopamine neurons. Further evaluation will reveal the mode of seeding, transfer (transynaptic versus retrograde) and possible recruitment of endogenous rat α-synuclein.

At 25th Annual Meeting of the Network for European CNS Transplantation & Restoration held in Lund, Sweden, December 9-11, 2015.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/speed-and-severity-of-toxicity-induced-by-pre-formed-synuclein-fibrils-in-rat-brain-is-enhanced-by-synuclein-overexpression/