TOWARD UNDERSTANDING THE PATHOGENIC MECHANISMS IN GELSOLIN-RELATED AMYLOIDOSIS - IN-VITRO EXPRESSION REVEALS AN ABNORMAL GELSOLIN FRAGMENT

Gelsolin-related amyloidosis, also called familial amyloidosis, Finnis h type (FAF) is an autosomal dominantly inherited disorder characteriz ed by progressive polyneuropathy and corneal lattice dystrophy. All th e analyzed patients are found to carry a nucleotide subsitution of A o r T for G(654) in their gelsolin gene, which at the protein level resu lts in the conversion of the 187 amino acid residue, aspartic acid, to asparagine or tyrosine, respectively. In this study, we transfected m ammalian mesenchymal COS-1 cells with a derivative of the expression v ector pCD-X containing cDNA coding for the wild-type (D-187) and mutan t forms (N-187 and Y-187) of plasma gelsolin. Both disease-associated mutant forms of gelsolin were found to be abnormally processed, which led to the secretion of an aberrant 68 kDa gelsolin fragment into the culture media. This fragment most probably represents a carboxy-termin al part of the protein and contains the suggested amyloid-forming sequ ence. Initial data were also obtained for involvement of a meta;loendo protease in the pathologic processing. This aberrant proteolysis is li kely to represent a crucial initiator step in the cascade resulting in amyloid accumulation in patients' tissues.