Targeting protein aggregation for the treatment of degenerative diseases
NATURE REVIEWS DRUG DISCOVERY(2015)
摘要
Key Points The misfolding and/or misassembly of more than 30 human proteins — for example, transthyretin, immunoglobulin light chain, serum amyloid A and amyloid-β — into various aggregate structures, a process known as amyloidogenesis, cause a range of degenerative disorders, collectively called amyloid diseases. Amyloidogenesis is a dynamic process; thus, the protein aggregates produced adopt a range of structures ranging from small, relatively unstructured oligomers to structurally well-defined cross-β-sheet amyloid fibrils. Some structures may only be produced in humans. Although there is mounting genetic and pharmacological evidence that the process of protein aggregation is an important driver of neurodegeneration, a structure–proteotoxicity relationship is lacking for all human amyloid diseases. Moreover, we do not understand how the process of aggregation leads to the loss of postmitotic tissue in any human amyloid disease. In this Review, we summarize current and emerging strategies to ameliorate degenerative disorders associated with protein aggregation, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Potential therapeutic strategies for degenerative disorders associated with protein aggregation include: protein stabilization to prevent the conformational changes that enable aggregation, protein reduction to lower the concentration of the aggregation-prone protein and thereby slow aggregation, aggregate clearance or remodelling to reduce proteotoxicity, cellular proteostasis network adaptation to enhance proteome quality control, and reducing seeding and cell-to-cell spreading.
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关键词
drug discovery,protein aggregation
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