Age-related increase of alpha-synuclein oligomers is associated with motor disturbances in L61 transgenic mice

The pathogenesis of Parkinson's disease involves fibrillization and deposition of alpha-synuclein (alpha-syn) into Lewy bodies. Accumulating evidence suggests that alpha-syn oligomers are particularly neurotoxic. Transgenic (tg) mice overexpressing wild-type human alpha-syn under the Thy-1 promoter (L61) reproduce many Parkinson's disease features, but the pathogenetic relevance of alpha-syn oligomers in this mouse model has not been studied in detail. Here, we report an age progressive increase of alpha-syn oligomers in the brain of L61 tg mice. Interestingly, more profound motor symptoms were observed in animals with higher levels of membrane-bound oligomers. As this tg model is X-linked, we also performed subset analyses, indicating that both sexes display a similar age-related increase in alpha-syn oligomers. However, compared with females, males featured increased brain levels of oligomers from an earlier age, in addition to a more severe behavioral phenotype with hyperactivity and thigmotaxis in the open field test. Taken together, our data indicate that alpha-syn oligomers are central to the development of brain pathology and behavioral deficits in the L61 tg alpha-syn mouse model. Joint first authors: Sahar Roshanbin and Agata Aniszewska