Aggregate formation and toxicity by wild‐type and R621C synphilin‐1 in the nigrostriatal system of mice using adenoviral vectors

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Abstract
Synphilin‐1 was described as a protein interacting with α‐synuclein and is commonly found in Lewy bodies, the pathological hallmark of Parkinson’s disease (PD). Our group has previously described and characterized in vitro a mutation in the synphilin‐1 gene (R621C) in PD patients. Providing the first characterization of synphilin‐1 expression in an animal model, we here used adenoviral gene transfer to study the effects of wild‐type (WT) and R621C synphilin‐1 in dopaminergic neurons in mouse brain. As synphilin‐1 is commonly used to trigger aggregation of α‐synuclein in cell culture, we investigated not only non‐transgenic C57Bl/6 mice but also A30P‐α‐synuclein transgenic animals. Both WT synphilin‐1 and R621C synphilin‐1 led to the formation of Thioflavine‐S positive inclusions in C57Bl/6 mice and degeneration of dopaminergic neurons in the substantia nigra. R621C synphilin‐1 induced more aggregate formation than WT synphilin‐1 in A30P‐α‐synuclein transgenic mice, consistent with the role of the R621C mutation as a susceptibility factor for PD. Synphilin‐1 expression may be used to improve current mouse models of PD, as it induced both the formation of aggregates and degeneration of dopaminergic neurons, two core characteristics of PD that have not been well reproduced with expression of α‐synuclein.