title: Cells of the neuronal lineage play a major role in the generation of amyloid precursor fragments in gelsolin-related amyloidosis.
abstract: Gelsolin-related amyloidosis or familial amyloidosis, Finnish type (FAF) (OMIM No105120) is a hereditary amyloid disease caused by a mutation in a precursor protein for amyloid (gelsolin) and characterized by corneal dystrophy and polyneuropathy. In vitro expression of the FAF-mutant (Asp187 --> Asn/Tyr) secretory gelsolin in COS cells leads to generation of an aberrant polypeptide presumably representing the precursor for tissue amyloid. Here, we provide evidence that this abnormal processing results from defective initial folding of the secreted FAF gelsolin due to the lack of the Cys188-Cys201 disulfide bond, normally formed next to the FAF mutation site. We compared cells of different tissue origin and discovered a dramatic difference between the amount of cleavage of FAF gelsolin to the amyloid precursor in neuronal and non-neuronal cells. More than half of the mutant gelsolin was cleaved in PC12 and in vitro differentiated human neuronal progenitor cells. In contrast, human fibroblasts and Schwannoma cell cultures showed only a limited capacity to cleave FAF gelsolin, although the cleavage mechanism per se seems to be similar in the various cell types. The present findings of processing and distribution of secreted FAF gelsolin in the neuronal cells emphasize the role of neurons in the tissue pathogenesis of this amyloid polyneuropathy.
authors.affiliation: Department of Human Molecular Genetics, Institute of Biomedicine, University of Helsinki and National Public Health Institute, 00300 Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Paunio
authors.forename: H
authors.initials: H
authors.lastname: Kangas
authors.forename: O
authors.initials: O
authors.lastname: Heinonen
authors.forename: M H
authors.initials: MH
authors.lastname: Buc-Caron
authors.forename: J J
authors.initials: JJ
authors.lastname: Robert
authors.forename: S
authors.initials: S
authors.lastname: Kaasinen
authors.forename: I
authors.initials: I
authors.lastname: Julkunen
authors.forename: J
authors.initials: J
authors.lastname: Mallet
authors.forename: L
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D017772:Amyloid Neuropathies / Q000235:genetics* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D019556:COS Cells; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D004285:Dogs; D018260:Gelsolin / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000096:biosynthesis*; D051381:Rats; D013234:Stem Cells / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D004220:Disulfides; D018260:Gelsolin; D010446:Peptide Fragments; D003545:Cysteine