Amyloidoses are a group of diseases where abnormal fibrillar
protein deposits accumulate in patients' tissues. In
familial amyloidosis of the Finnish type (FAF), or
gelsolin-related amyloidosis, the
amyloid subunit protein consists of
gelsolin peptides of
amino acids 173-243 with the disease causing substitution at Asp187.
Gelsolin is an actin-modulating
protein and exists in both secretory and intracellular forms both encoded by a single gene in chromosome 9. We have previously shown that the FAF-associated forms of secretory
gelsolin carrying the Asp187Asn or Asp187Tyr mutations are abnormally processed in cells, resulting in the secretion of an aberrant 68 kDa carboxyterminal fragment. Here we demonstrate by N-terminal sequencing that the amino terminus of this abnormal fragment is the
amino acid 173 and thus represents the N-terminus of the FAF
amyloid. We also provide evidence that the same truncated
gelsolin can be found among the aberrant
gelsolin fragments detected in patients' CSF. Finally, we also expressed the FAF-associated forms of intracellular
gelsolin in COS-1 cells, and found no abnormality in their processing opposite to secretory form. Our results provide strong evidence that the secretory
gelsolin is solely responsible for the
amyloid formation in FAF.