Familial amyloid polyneuropathy is a heritable condition in which the protein transthyretin misfolds, leading to the formation of amyloid fibrils--proteinaceous deposits that interfere with nerve and muscle function. Transthyretin, a protein secreted by the liver, normally forms complexes containing four identical transthyretins. In this tetramer form, the protein carries out its conventional role as a transporter of thyroid hormone and vitamin A.

But when the gene for an abnormal form of transthyretin (such as the protein's "V30M" mutant) is inherited from at least one parent, the tetramers become unstable and dissociate. The individual monomer molecules then partially unfold and aggregate to form disease-associated amyloid fibrils.

Another mutated form of transthyretin, called "T119M," has been known for several years to have the opposite effect: It lends extra stability to transthyretin tetramers. Now, in experiments on tetramers with defined V30M and T119M stoichiometry, a Scripps Research Institute group has determined that increasing the number of T119M units in a tetramer not only increases tetramer stability proportionally but also can completely overwhelm the dissociative influence of the V30M units. The work was carried out by postdoc Per Hammarström, visiting medical student Frank Schneider, and chemistry professor Jeffery W. Kelly [Science, 293, 2459 (2001)].

The researchers show that protein-protein interactions in the tetramer between the "good" and "bad" transthyretin mutants can prevent the complex from breaking down and stop amyloid fibrils from forming, a result not previously demonstrated. Essentially, Kelly and coworkers find that one mutated form of the protein prevents misfolding induced by another mutated form--a phenomenon called "trans-suppression of misfolding." Cis-suppression, in which a mutated site inhibits misfolding induced by a second site within the same protein chain, has been demonstrated previously by several groups.

The new results "explain how trans-suppression works in vitro and likely in humans," Kelly says. The findings also suggest that an ameliorative effect could be obtained by introducing T119M-like proteins into the body by injection or, more speculatively, by gene therapy targeted at liver cells.

Small-molecule inhibitors of transthyretin amyloid formation identified earlier by Kelly's group and the macromolecular inhibitor T119M "have a common molecular mechanism," Kelly says. "They both significantly increase the activation barrier for tetramer dissociation, preventing misfolding and disease."

Associate professor of neurology Peter T. Lansbury Jr. at Harvard Medical School says the Scripps study is "a beautiful demonstration" of how detailed biophysics can explain phenomena such as inhibition of protein misfolding. "It suggests a therapeutic strategy--stabilization of the tetramer, which the Kelly group is already pursuing with small molecules," Lansbury says. "And it provides more circumstantial evidence that abnormal aggregation causes familial amyloid polyneuropathy and, by extrapolation, other amyloid diseases."

Professor of neurosciences and pathology Eliezer Masliah of the University of California, San Diego, and coworkers will also soon report that -synuclein inhibits -synuclein aggregation, a process associated with Parkinson's disease. The inhibitory mechanism appears to be similar to that for transthyretin.

The trans-suppression approach may also be generalizable to a broad range of other protein misfolding disorders. "Other amyloid proteins that are either misfolded or disordered could be prevented from fibrillizing by an analogous mechanism," Lansbury says.

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Copyright © 2001 American Chemical Society