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Experimental Genetics Group
Biochim Biophys Acta. 2006 Mar;1762(3):312-8. Griffioen G1*, Duhamel H1, Van Damme N1, Pellens K2, Zabrocki P2, Pannecouque C3, van Leuven F4, Winderickx J2, Wera S1. 1N.V. reMYND, Leuven, Belgium. 2Laboratory of Functional Biology, Institute of Botany and Microbiology, Katholieke Universiteit Leuven, Leuven-Heverlee, Belgium. 3Department of Microbiology en Immuno, Katholieke Universiteit Leuven, Leuven, Belgium. 4Experimental Genetics Group LEGT_EGG, Dept. Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium. *Corresponding author. 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.  FULL TEXT |
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