In the current issue of the Proceedings of the National Academy of Sciences, (http://www.pnas.org/cgi/content/abstract/102/26/9394) Mayo researchers report that under certain genetic conditions, key proteins are not formed properly -- they are "misfolded." When misfolding happens, the quality-control process in the cell detects the misfolded proteins and tags them for immediate destruction or quarantines them in a "cellular trash can" known as an aggresome (last syllable rhymes with "foam"). Whether destroyed or aggregated into the aggresome, the effect is the same: the patient's body suffers a protein deficit that disrupts the enzyme that metabolizes thiopurine.
"Our finding is surprising because the aggresome is a new kind of mechanism to study to explain this. It's quite different from what we were thinking even a few years ago," says Liewei Wang, M.D., Ph.D., lead Mayo researcher in the study. "People are still debating what its function really is, but it appears to play a role here by receiving misfolded proteins."
Significance of the Research
"Nobody has shown before that the aggresome plays a role in thiopurine metabolism, and it's a significant contribution," says Richard Weinshilboum, M.D., the Mayo Clinic researcher who first described the genetically variable response to thiopurine drugs over 20 years ago. "From a clinical point of view, the genetic test we developed at Mayo to predict response to thiopurine drugs has been