Cell based screening of inhibitors of transthyretin aggregation
| Autor: | Natàlia Reixach, Sara L. Adamski-Werner, James A. Koziol, Jeffery W. Kelly, Joel N. Buxbaum |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
endocrine system
Cell Survival Cell Biophysics Drug Evaluation Preclinical Biology Biochemistry Amyloid disease Methionine In vivo Cell Line Tumor Stilbenes medicine Extracellular Humans Prealbumin Cell Lineage Cytotoxicity Molecular Biology Cell damage Neurons Amyloidosis Anti-Inflammatory Agents Non-Steroidal nutritional and metabolic diseases Valine Cell Biology medicine.disease Diflunisal Transthyretin medicine.anatomical_structure Resveratrol Microfibrils biology.protein |
| Zdroj: | Biochemical and biophysical research communications. 348(3) |
| ISSN: | 0006-291X |
| Popis: | The amyloidoses are the extracellular subset of a group of diseases in which in vivo protein misfolding leads to a pathologic gain of function, i.e., aggregation leading to protein deposition, with subsequent tissue damage. Wild-type and mutant transthyretins (TTR) are the etiologic agents in prototypic systemic amyloidoses. We describe a cell-based assay that measures the cytotoxicity of physiologic concentrations of the amyloidogenic Val30Met TTR variant (V30M TTR) using cells of the same lineage as the in vivo tissue target of amyloid deposition. We have utilized the assay to screen small molecules for their capacity to inhibit the TTR-induced cell damage. We compared the inhibitory activity of each compound with its ability to prevent TTR fibril formation in vitro. Our results emphasize the importance of screening compounds under physiologic conditions. Moreover, if a common conformational intermediate is responsible for cell death in all the amyloid diseases, the cell-based assay has the potential to aid in the discovery of compounds useful in the treatment of amyloidoses caused by other misfolded proteins as well as those caused by TTR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect