Trans-suppression of misfolding in an amyloid disease

The transthyretin (TTR) amyloid diseases, representative of numerous misfol ding disorders, are of considerable interest because there are mutations th at cause or suppress disease. The Val(30) --> Met(30) (V30M) TTR mutation i s the most prevalent cause of familial amyloid polyneuropathy in heterozygo tes, whereas a Thr(119) ---> Met(119) (T119M) mutation on the second TTR al lele protects V30M carriers from disease. Here, we show that the incorporat ion of one or more T119M TTR subunits into a predominantly V30M tetramer st rongly stabilized the! mixed tetramer against dissociation. Dissociation is required for amyloid formation, so these findings provide a molecular expl anation for intragenic trans-suppression of amyloidosis. The data also sugg est a potential therapeutic strategy, provide insight into tissue-specific deposition and amyloid composition, and support the validity of the amyloid hypothesis in human disease.