Adapting the Chemistry and/or Biology of Proteostasis to Ameliorate Protein Aggregation Diseases

The cellular protein homeostasis, or proteostasis network, regulates proteome function by controlling ribosomal protein synthesis, chaperone and chaperonin mediated protein folding, protein trafficking, protein degradation and related processes. Stress responsive signaling pathways match proteostasis network capacity with demand in each subcellular compartment to maintain or alter cellular homeostasis. The beginning of the seminar will focus on how the proteostasis network can be adapted pharmacologically through unfolded protein response arm‐selective signaling to alleviate the gain‐of‐toxic‐function diseases, including light chain amyloidosis and the transthyretin amyloidosis, where excessive secretion of misfolding and aggregation of proteins leads to a degenerative phenotypes. This strategy will be contrasted with high affinity small molecule binding to the normally folded structural ensemble of an aggregation‐prone protein inside and/or outside of the cell to stabilize the native state, lowering the population of misfolded, misassembly competent states that lead to aggregates, including amyloid fibrils. Lastly, we will cover the progress made to discover autophagy activators. These drug candidates are envisioned to be generally useful for ameliorating multiple neurodegenerative diseases based on human genetic evidence. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .