A yeast-based model of alpha-synucleinopathy identifies compounds with therapeutic potential.
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.
Griffioen
Gerard
G
N.V. reMYND, Minderbroedersstraat 12, B-3000 Leuven, Belgium. gerard.griffioen@remyund.be
Duhamel
Hein
H
Van Damme
Nele
N
Pellens
Klaartje
K
Zabrocki
Piotr
P
Pannecouque
Christophe
C
van Leuven
Fred
F
Winderickx
Joris
J
Wera
Stefaan
S
D001927:Brain Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008670:Metals / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
D061945:Caspase Inhibitors; D005419:Flavonoids; D008670:Metals; D018696:Neuroprotective Agents; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; D002392:Catechin; C045651:epigallocatechin gallate; D020169:Caspases; C456272:MCA1 protein, S cerevisiae