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Title: A yeast-based model of alpha-synucleinopathy identifies compounds with therapeutic potential
Authors: Griffioen, Gerard ×
Duhamel, Hein
Van Damme, Nele
Pellens, Klaartje
Zabrocki, Piotr
Pannecouque, Christophe
Van Leuven, Freddy
Winderickx, Joris
Wera, Stefaan #
Issue Date: Mar-2006
Publisher: Elsevier
Series Title: Biochimica et Biophysica Acta. Molecular Basis of Disease vol:1762 issue:3 pages:312-318
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.
URI: 
ISSN: 0925-4439
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Associated Laboratories - miscellaneous (-)
Laboratory for Functional Biology (-)
Molecular Physiology of Plants and Micro-organisms Section - miscellaneous
Laboratory of Virology and Chemotherapy (Rega Institute)
Laboratory of Molecular Biology of Leukemia
× corresponding author
# (joint) last author

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