A yeast-based model of alpha-synucleinopathy identifies compounds with therapeutic potential |
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Authors: | Griffioen Gerard Duhamel Hein Van Damme Nele Pellens Klaartje Zabrocki Piotr Pannecouque Christophe van Leuven Fred Winderickx Joris Wera Stefaan |
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Institution: | N.V. reMYND, Minderbroedersstraat 12, B-3000 Leuven, Belgium. gerard.griffioen@remyund.be |
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Abstract: | We have developed a yeast-based model recapitulating neurotoxicity of alpha-synuclein fibrilization. This model recognized metal ions, known risk factors of alpha-synucleinopathy, as stimulators of alpha-synuclein aggregation and cytotoxicity. Elimination of Yca1 caspase activity augmented both cytotoxicity and inclusion body formation, suggesting the involvement of apoptotic pathway components in toxic alpha-synuclein amyloidogenesis. Deletion of hydrophobic amino acids at positions 66-74 in alpha-synuclein reduced its cytotoxicity but, remarkably, did not lower the levels of insoluble alpha-synuclein, indicating that noxious alpha-synuclein species are different from insoluble aggregates. A compound screen aimed at finding molecules with therapeutic potential identified flavonoids with strong activity to restrain alpha-synuclein toxicity. Subsequent structure-activity analysis elucidated that these acted by virtue of anti-oxidant and metal-chelating activities. In conclusion, this yeast-cell model as presented allows not only fundamental studies related to mechanisms of alpha-synuclein-instigated cellular degeneration, but is also a valid high-throughput identification tool for novel neuroprotective agents. |
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