Transthyretin in senile systemic amyloidosis and familial amyloidotic polyneuropathy

The amyloidoses comprise a heterogeneous group of disorders characterized by the deposition of fibrillar, proteinaceous amyloid deposits in various organs and tissues. To date, 17 different proteins of various sizes have been identified as amyloid proteins. Irrespective of the specific protein comprising the amyloid fibrils, the fibrils are all about 10 nm wide and of indefinite length.In the most common familial form of amyloidosis, familial amyloidotic polyneuropathy (FAP), the amyloid fibril protein is the plasma protein transthyretin (TTR). In FAP type I, which is the type found in Sweden, there is a mutation in the TTR gene leading to the substitution of a methionine for valine at position 30. This mutation leads to a form of amyloidosis characterized by polyneuropathy starting in the lower limbs and usually slowly progressing until death occurs. Another TTR-derived form of amyloidosis is senile systemic amyloidosis (SSA). This form of amyloidosis is present in about 25% of people 80 years of age or older. In SSA, amyloid is deposited mainly in the heart but deposits are also found in many other organs.In this study it is demonstrated that normal TTR can form fibrils in vitro. Fibril formation studies were also performed in vitro with synthetic peptides corresponding to parts of the TTR amino acid sequence. These results indicate that TTR peptides with 13-strand secondary structure are fibrillogenic in vitro and are likely important in in vivo amyloidogenesis.The TTR amino acid and DNA sequences in cases with SSA were determined and found to be normal, thus showing that no mutation is necessary for development of this form of amyloidosis. However, cleavage of TTR may be important in fibrillogenesis since TTR fragments lacking 45-51 N-terminal amino acid residues predominated in the amyloid.Antigenic epitopes exposed on normal TTR and TTR derived from amyloid deposits were also examined. The 13-strand H was found to be exposed in amyloid TTR and not in normal TTR, thus suggesting a changed structural conformation of TTR in amyloid fibrils.