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- W2000233418 abstract "The process of protein misfolding and aggregation into insoluble deposits is associated with a wide range of human disorders known as amyloidoses that include Alzheimerś disease. The quest for molecules that can modulate the protein aggregation process has thus far been approached using in vitro aggregation assays. Successful molecules are evaluated for reduction of amyloid induced toxicity in cell culture, and the best hits are tested in animal models of the disease. So far, none of the small molecules that been identified using these in vitro assays have proceeded to clinical trials and have exhibited a therapeutic benefit. One the reasons that underlie this problem is that the methods used for evaluation of such compounds are not very representative of the in vivo situation. To date, a quantitative in vivo model of protein misfolding and aggregation is still missing. We designed a sensor of intracellular protein misfolding and aggregation, based on measuring the enzymatic activity of fusion proteins, in which intracellular or extracellular reporter enzymes are fused to amyloidogenic proteins. Aggregation of the chimeric reporter results in reduction of enzymatic activity. One main advantage of our sensor versus existing technologies is that enzymatic activity is an extremely sensitive detection method, which is suitable for HTS and can be quantified not only in cell culture but also in the whole, live animal. We find that our system is very sensitive and can, with dynamic range of two orders of magnitude, measure intra- and extra-cellular protein aggregation in human cell lines and primary neuronal cultures, as well as in the CNS of mice. It is also up to date the first quantitative cellular sensor for extracellular protein aggregation. Our data show that this system is useful to screen libraries of small molecules or genetic modifiers that can interfere, block or reverse the process of protein aggregation in mammalian neurons. This in vivo system is also able to provide exact measurements that can be used for modeling of the aggregation process in a complex cellular environment and to develop prediction algorithms based on those data." @default.
- W2000233418 created "2016-06-24" @default.
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- W2000233418 date "2011-07-01" @default.
- W2000233418 modified "2023-09-27" @default.
- W2000233418 title "P2-460: A quantitative cellular sensor of protein aggregation" @default.
- W2000233418 doi "https://doi.org/10.1016/j.jalz.2011.05.1332" @default.
- W2000233418 hasPublicationYear "2011" @default.
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