H. Kangas et al., IN-VITRO EXPRESSION ANALYSIS SHOWS THAT THE SECRETORY FORM OF GELSOLIN IS THE SOLE SOURCE OF AMYLOID IN GELSOLIN-RELATED AMYLOIDOSIS, Human molecular genetics, 5(9), 1996, pp. 1237-1243
Amyloidoses are a group of diseases where abnormal fibrillar protein d
eposits accumulate in patients' tissues. In familial amyloidosis of th
e Finnish type (FAF), or gelsolin-related amyloidosis, the amyloid sub
unit protein consists of gelsolin peptides of amino acids 173-243 with
the disease causing substitution at Asp187. Gelsolin is an actin-modu
lating protein and exists in both secretory and intracellular forms bo
th encoded by a single gene in chromosome 9. We have previously shown
that the FAF-associated forms of secretory gelsolin carrying the Asp18
7Asn or Asp187Tyr mutations are abnormally processed in cells, resulti
ng in the secretion of an aberrant 68 kDa carboxyterminal fragment. He
re 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 t
runcated gelsolin can be found among the aberrant gelsolin fragments d
etected in patients' CSF. Finally, we also expressed the FAF-associate
d forms of intracellular gelsolin in COS-1 cells, and found no abnorma
lity in their processing opposite to secretory form. Our results provi
de strong evidence that the secretory gelsolin is solely responsible f
or the amyloid formation in FAF.