Therapeutic Strategies Against Gain and Loss of Function Misfolding Diseases

The misfolding and/or misassembly of what is typically one protein inside the cell leads to gain of toxic function diseases such as Huntington's and Parkinson's disease, whereas extracellular misfolding and/or misassembly appears to cause analogous diseases known as the amyloidoses, including Alzheimer's disease and numerous rarer familial diseases. Mutations can also predispose a protein to misfold in the endoplasmic reticulum (ER), culminating in protein degradion by the proteasome–resulting in a loss of function disease. The most common mutations in proteins that cause Gaucher Disease and Cystic fibrosis have sufficient activity in their destination environment (the lysosome and the plasma membrane, respectively), that they could function there–if they were able to fold in the unique environment of the ER and exit this organelle. The seminar will start with an overview of the mechanistic insight that we and others have acquired from studying these diseases and then outline how this information has been utilized to develop small molecule therapeutic strategies to intervene in maladies that often lead to death within ten years of onset. The talk will close with the description of a recent discovery that mammalian cells make amyloid fibrils for functional purposes, illuminating the fine line between physiology and pathology that must be considered in envisioning and developing therapeutic strategies.