IN-VITRO EXPRESSION ANALYSIS SHOWS THAT THE SECRETORY FORM OF GELSOLIN IS THE SOLE SOURCE OF AMYLOID IN GELSOLIN-RELATED AMYLOIDOSIS

Citation
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
Citations number
38
Categorie Soggetti
Genetics & Heredity",Biology
Journal title
ISSN journal
09646906
Volume
5
Issue
9
Year of publication
1996
Pages
1237 - 1243
Database
ISI
SICI code
0964-6906(1996)5:9<1237:IEASTT>2.0.ZU;2-2
Abstract
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.