 |
News Search |
|
|
|
NSAIDs and Derivatives Keep Transthyretin in Its Place
|
|
|
|
|
|
31 January 2003. Transthyretin, like Aβ, is capable of forming amyloid fibrils, and can lead to systemic amyloidosis in families who have inherited particularly fibrillogenic forms of the protein. Curiously, some years ago, work from Jeffrey Kelly's lab at the Scripps Research Institute, La Jolla, California, showed that the nonsteroidal antiinflammatory drug (NSAID) flufenamic acid could inhibit transthyretin fibrillogenesis (Peterson, 1998). Now, reporting in today's Science, Kelly and colleagues offer an explanation as to how NSAIDs, such as diclofenac and its derivatives, prevent the growth of these toxic chains.
First author Per Hammerstrom and colleagues show that NSAIDs may function in a similar manner to a natural variant of the protein that ameliorates amyloidosis. By measuring the dissociation kinetics of transthyretin tetramers, Hammerstrom et al. were able to show that this "good" transthyretin, which has a methionine amino acid in place of a threonine at position 119, stabilizes the native form, preventing its dissociation into amyloidogenic monomers. When Hammerstrom et al. examined the kinetics of tetramer dissociation in the presence of diclofenac derivatives, they found that these analogues also stabilized the tetramers.
The data builds on previous crystallographic work from this group showing how NSAIDS can insinuate themselves into transthyretin tetramers, and suggest that these small molecules increase even further the energy barrier that prevents the tetramers from rapidly dissociating. It remains to be seen, however, whether similar treatments may work on other amyloidogenic proteins. "We are not certain that this approach will work for Alzheimer's disease," commented Kelly," but we would like to target the Aβ precursor protein because it does interact with a number of other proteins and does have small-molecule binding sites." In this regard it is worth noting that NSAIDs have recently been shown to lower Aβ42 levels in a manner that is independent of their action on cyclooxygenase (see ARF related news story).-Tom Fagan
Reference:
Hammarstrom P, Wiseman RL, Powers ET, Kelly JW. Prevention of Transthryetin amyloid disease by changing protein misfolding energetics. Science. 2003 January 31;299:713-716. Abstract
|
|
| |
|
Comments on News and Primary Papers |
|
|
| |
Comment by: David Teplow
|
|
|
Submitted 31 January 2003
| Permalink
|
Posted 31 January 2003
|
|
|
The Enron Collapse and Amyloid Formation
What, you might ask, could the Enron collapse have to do with amyloid formation? The answer is, everything, in a sense. If one takes an otherwise stable corporation and begins executing business strategies that destabilize it, the financial condition of the company begins to suffer. At early stages, the damage can be repaired, the company saved. However, once a critical point has been reached, the whole fabric of the business unravels. In today’s Science, Hammarstrom et al. demonstrate that this phenomenon is at the "core" of the process of transthyretin (TTR) amyloid assembly. Through the work of the Kelly group and others, it has been known that amino acid substitutions in TTR, or environmental conditions, could destabilize the normal tetramer "fold" of TTR, leading to tetramer dissociation and monomer destabilization (unraveling). The conformationally altered monomer then could assemble to form amyloid. In a compelling set of experiments, Hammarstrom now shows how small-molecule amyloid inhibitors can stabilize TTR. In addition,...
Read more
The Enron Collapse and Amyloid Formation
What, you might ask, could the Enron collapse have to do with amyloid formation? The answer is, everything, in a sense. If one takes an otherwise stable corporation and begins executing business strategies that destabilize it, the financial condition of the company begins to suffer. At early stages, the damage can be repaired, the company saved. However, once a critical point has been reached, the whole fabric of the business unravels. In today’s Science, Hammarstrom et al. demonstrate that this phenomenon is at the "core" of the process of transthyretin (TTR) amyloid assembly. Through the work of the Kelly group and others, it has been known that amino acid substitutions in TTR, or environmental conditions, could destabilize the normal tetramer "fold" of TTR, leading to tetramer dissociation and monomer destabilization (unraveling). The conformationally altered monomer then could assemble to form amyloid. In a compelling set of experiments, Hammarstrom now shows how small-molecule amyloid inhibitors can stabilize TTR. In addition, they examine the effects of the Thr119Met mutant of TTR, which is more resistant to amyloidogenesis and can work in trans to protect native TTR from unravelling.
The key to understanding the mechanics of these phenomena is summarized in Figure 4, which shows classic reaction coordinate diagrams for the dissociation of the TTR tetramer to an unfolded monomeric state capable of accessing amyloid formation pathways. Binding of a small molecule inhibitor to the TTR tetramer stabilizes it (i.e., it increases the activation energy for the tetramer-monomer transition). Binding of two inhibitors increases the activation energy further. The Thr199Met amino acid substitution also leads to maintenance of the tetramer, but not by tetramer stabilization, per se. Rather, Met199 DEstabilizes the transition state between tetramer and the folded monomer (increases the activation energy for the transition), making it much less likely that tetramer dissociation will occur. Bottom line: If one can decrease the energy of the ground state (here, the TTR tetramer), or increase the energy of the transition state, then there is a good chance that amyloidogenic tranformation can be prevented. This strategy should be applicable universally, e.g., with Aβ, α-synuclein, prion, etc. If only Ken Lay had read up on his thermodynamics!
 View all comments by David Teplow |
|
|
|
| |
Submit a Comment on this News Article |
|
|
|
|
|
Home
