التفاصيل البيبلوغرافية
| العنوان: |
A yeast-based model of α-synucleinopathy identifies compounds with therapeutic potential |
| المؤلفون: |
Piotr Zabrocki, Joris Winderickx, Stefaan Wera, Gerard Griffioen, Hein Duhamel, Christophe Pannecouque, Fred Van Leuven, Klaartje Pellens, Nele Van Damme |
| المصدر: |
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. (3):312-318 |
| بيانات النشر: |
Elsevier B.V. |
| مصطلحات موضوعية: |
Saccharomyces cerevisiae Proteins, Protein-aggregation, Recombinant Fusion Proteins, animal diseases, Parkinson's disease, Saccharomyces cerevisiae, Protein aggregation, Models, Biological, Neuroprotection, Catechin, α-synuclein, Risk Factors, mental disorders, medicine, Humans, Cytotoxicity, Molecular Biology, Caspase, Flavonoids, chemistry.chemical_classification, Brain Diseases, Molecular Structure, biology, Neurotoxicity, biology.organism_classification, medicine.disease, Caspase Inhibitors, Yeast, Amino acid, nervous system diseases, Neuroprotective Agents, Biochemistry, chemistry, nervous system, Metals, Caspases, alpha-Synuclein, biology.protein, Molecular Medicine, Phenotype-based model |
| الوصف: |
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. |
| اللغة: |
English |
| تدمد: |
0925-4439 |
| DOI: |
10.1016/j.bbadis.2005.11.009 |
| URL الوصول: |
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::71fb075a6ae85b14843651b731396e37 |
| Rights: |
OPEN |
| رقم الانضمام: |
edsair.doi.dedup.....71fb075a6ae85b14843651b731396e37 |
| قاعدة البيانات: |
OpenAIRE |