Sci. Aging Knowl. Environ., 10 October 2001
Vol. 2001, Issue 2, p. or18


Trans-Suppression of Misfolding in an Amyloid Disease

Per Hammarstr�m, Frank Schneider, and Jeffery W. Kelly;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.

Full Text

Science of Aging Knowledge Environment. ISSN 1539-6150