Tiffany A. Thibaudeau, Raymond T. Anderson & David M. Smith* “A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers.” Nature Communications 9; March, 2018. doi:10.1038/s41467-018-03509-0
The Smith lab has published a research article in Nature Communications demonstrating that a common mechanism for the impairment of protein degradation may underlie many neurodegenerative diseases, like Alzheimer’s, Parkinson’s and Huntington’s disease. Tiffany Thibaudeau a graduate student in Dr. Smith’s lab and lead Author of this study was able to demonstrate that a specific misfolded and oligomerized proteins that contribute to Alzheimer’s, Parkinson’s and Huntington’s diseases are actually potent inhibitors of the proteasome, the cells primary protein degradation machinery. Not only did Tiffany demonstrate the type of oligomers that inhibit the proteasome, she also carefully dissected the mechanism by which these oligomers do this with the assistance of her co-author Raymond Anderson. Though it’s actually far more complicated than this, you can think of the proteasome as a gated garbage disposal. If you want to get rid of your proteins you can open the gate to the proteasome and throw your proteins in on at a time. They found that these “toxic” oligomers can actually block the gate so it can’t be opened, and if you can’t open the gate, then you can’t degrade your proteins, and then they start building up and wreaking havoc in the cell, including further inhibiting the proteasome. Understanding that this occurs in neurodegenerative disease and the detailed mechanism that is involved will allow the Smith lab and others to design small molecules that can act like drugs to prevent the toxic oligomers from inhibiting the proteasome. Most interestingly the oligomeric conformations that inhibits proteasome so well, is a conformation that is found in many types of neurodegenerative diseases. This greatly broadens the scope of this study, and demonstrates that this mechanism for impairing proteasome function, could be very general and thus drugs that counteract this mechanism could be relevant to many neurodegenerative diseases. It’s not often that you can imagine a single drug to have such a wide impact on so many diseases.