The pathophysiology of Parkinson's disease is characterized by the abnormal accumulation of á-synuclein (á-Syn), eventually resulting in the formation of Lewy bodies and neurites in surviving neurons in the brain. Although á-Syn aggregation has been extensively studied in vitro, there is limited in vivo knowledge on á-Syn aggregation. Here, we used the powerful genetics of Drosophila melanogaster and developed an in vivo assay to monitor á-Syn accumulation by using a bimolecular fluorescence complementation assay. We found that both genetic and pharmacologic manipulations affected á-Syn accumulation. Interestingly, we also found that alterations in the cellular protein degradation mechanisms strongly influenced á-Syn accumulation. Administration of compounds identified as risk factors for Parkinson's disease, such as rotenone or heavy metal ions, had only mild or even no impact on á-Syn accumulation in vivo. Finally, we show that increasing phosphorylation of á-Syn at serine 129 enhances the accumulation and toxicity of á-Syn. Altogether, our study establishes a novel model to study á-Syn accumulation and illustrates the complexity of manipulating proteostasis in vivo.-Prasad, V., Wasser, Y., Hans, F., Goswami, A., Katona, I., Outeiro, T. F., Kahle, P. J., Schulz, J. B., Voigt, A. Monitoring á-synuclein multimerization in vivo.
Amyloid Animals