The cellular protein homeostasis, or proteostasis, network regulates proteome function by controlling ribosomal protein synthesis, chaperone- and enzyme-mediated protein folding vs. degradation, protein trafficking, and the like. Stress-responsive signaling pathways match proteostasis network capacity with demand in each subcellular compartment to maintain cellular homeostasis. The beginning of the seminar will focus on adaptation of the proteostasis network through activation of stress-responsive signaling pathways to alleviate loss-of-function diseases. The second part of the seminar will focus on how stress-responsive signaling pathway activation ameliorates degenerative maladies linked to aggregation. The third part of the talk will focus on a chemical strategy to restore proteostasis, wherein small molecule kinetic stabilizers produced by structure-based drug design are employed to halt the progression of peripheral and autonomic neuropathy in familial amyloid polyneuropathy caused by transthyretin aggregation. The last part of the seminar will focus on what we have learned about the etiology of amyloid diseases.

Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases

244th National Meeting (2012)

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