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© 1994 Oxford University Press

OTHER

Toward understanding the pathogenic mechanisms in gelsolin-related amyloidosis: in vitro expression reveals an abnormal gelsolin fragment

Tllna Paunlo*, Hannele Kangas, Nisse Kalkklnen1, Matti Haltia2, Jorma Palo3 and Leena Peltonen

Department of Human Molecular Genetics, National Public Health Institute Mannerheimintie 166, 00300 Helsinki 1Institute of Biotechnology, University of Helsinki Valimotie 7, 00380 Helsinki 2Department of Pathology, University of Helsinli Haartmaninkatu 4, 00280 Helsinki, Finland 3Department of Neurology, University of Helsinli Haartmaninkatu 4, 00280 Helsinki, Finland

*To whom correspondence should be addressed

Received September 1, 1994; Accepted September 23, 1994

Gelsolln-related amyloldosls, also called familial amyloldosls, Finnish type (FAF) Is an autosomal dominantly Inherited disorder characterized by progressive polyneuropathy and corneal lattice dystrophy. All the analyzed patients are found to carry a nucleotlde subsltutlon of A or T for G654 In their gelsolln gene, which at the protein level results In the conversion of the 187 amino acid residue, aspartic acid, to asparaglne or tyrosine, respectively. In this study, we transfected mammalian mesenchymal COS-1 cells with a derivative of the expression vector pCD-X containing cDNA coding for the wild-type (D187) and mutant forms(N187 and Y187) of plasma gelsolln. Both disease-associated mutant forms of gelsolln 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-termlnal part of the protein and contains the suggested amyloid-forming sequence. Initial data were also obtained for Involvement of a metalloendoprotease in the pathologic processing. This aberrant proteolysis is likely to represent a crucial Initiator step in the cascade resulting in amyloid accumulation in patients' tissues.


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