Sci. Aging Knowl. Environ., 10 October 2001
Trans-Suppression of Misfolding in an Amyloid Disease
Per Hammarstr�m, Frank Schneider, and Jeffery W. Kellyhttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/2/or18
Abstract: Science 293, 2459-2462 (2001).
The transthyretin (TTR) amyloid diseases, representative of numerous misfolding disorders, are of considerable interest because there are mutations that cause or suppress disease. The Val30>Met30 (V30M) TTR mutation is the most prevalent cause of familial amyloid polyneuropathy in heterozygotes, whereas a Thr119>Met119 (T119M) mutation on the second TTR allele protects V30M carriers from disease. Here, we show that the incorporation of one or more T119M TTR subunits into a predominantly V30M tetramer strongly stabilized the mixed tetramer against dissociation. Dissociation is required for amyloid formation, so these findings provide a molecular explanation for intragenic trans-suppression of amyloidosis. The data also suggest a potential therapeutic strategy, provide insight into tissue-specific deposition and amyloid composition, and support the validity of the amyloid hypothesis in human disease.
Science of Aging Knowledge Environment. ISSN 1539-6150