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
- Peterson SA, Klabunde T, Lashuel HA, Purkey H, Sacchettini JC, Kelly JW. Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12956-60. PubMed.
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- Hammarström P, Wiseman RL, Powers ET, Kelly JW. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science. 2003 Jan 31;299(5607):713-6. PubMed.