Wednesday, July 16, 2008

From The Lab -- July

By Dr. Malcolm Leissring, Mayo Clinic Jacksonville

I am pleased to announce that work in the lab, supported by The Unforgettable Fund, was just published in the pages of a very prestigious journal: the Proceedings of the National Academy of Sciences!!

The first author of the paper was Marie Neant-Fery, a summer intern from the University of Paris. Those of you who kindly donated to The Unforgettable Fund supported her internship, and so in a very real way contributed to this very important study. Thank you for your generosity!!! We have another student in the lab, Christelle Cabrol, also from the University of Paris and also paid for by The Unforgettable Fund, so we're hoping for a repeat performance.

The title of the paper is “Molecular basis for the thiol sensitivity of insulin-degrading enzyme”, which probably isn’t to revealing to many readers of this blog, so allow me to translate.
As most of you following my work will know by now, insulin-degrading enzyme (IDE) is an enzyme that can degrade the amyloid ß-protein (Aß), the sticky protein fragment that accumulates in the brains of patients with Alzheimer’s disease. Because IDE degrades Aß, anything that makes it work less well could lead to elevated Aß, which is known to cause Alzheimer’s disease. There’s some evidence that IDE does indeed work less well as we age, something that may directly link Alzheimer’s to the aging process.

It turns out that IDE is inactivated irreversibly by certain chemical reactions—oxidative damage, essentially—that we know occur increasingly with age. The fact that IDE was vulnerable to this kind of damage was known in a general sort of way, but we did not know exactly what the cause was. In this recent paper, we showed exactly how this oxidative damage occurs in IDE, at the detailed, molecular level. This is a classic example of “reductionistic” science—that is, science that seeks to get at the absolutely most fundamental possible description of a phenomenon—in this case, the molecular basis for IDE’s thiol sensitivity (hence the title).

Knowing these details is important for a couple of reasons. First, it solves what was a decades-old riddle. IDE was originally misclassified as a very different type of enzyme based on its sensitivity to the particular kind of oxidative damage studied in this paper.

Second, and more importantly for our understanding of Alzheimer’s disease and possibly also diabetes, we now know precisely the kind of molecular changes that will inactivate IDE, which will enable future studies aimed at stopping this process or understanding things that trigger it. Potentially, it could lead to the development of biomarkers for IDE function that may indicate risk for disease.

Third, rather unexpectedly, we learned a very interesting thing about the way IDE functions. IDE has 13 cysteines (damage-prone amino acids), which are located all over the molecule (see Figure). To figure out which cysteine(s) was/were most vulnerable to damage, we made mutants of IDE that contain just a single cysteine—with the other 12 mutated to another, damage-resistant amino acid. These “single-cysteine” mutants could be treated with a certain chemical, which would cause that chemical to attach itself to the cysteine residue, the location of which we knew precisely.

It turns out that chemically modifying one cysteine in particular (Cys590) leads to a very surprising result—it causes IDE to degrade Aß faster! More important still, this same chemical modification had no effect on IDE’s ability to degrade insulin. This result is important, because it suggests that we might eventually be able to discover drugs that accomplish the same thing—which is exactly what we want to treat Alzheimer’s disease.

Back to work!

1 comment:

  1. I find this so informative. My father has Alzheimer's and I starting to research more and more. Thank you for the information.