CELLS OF THE NEURONAL LINEAGE PLAY A MAJOR ROLE IN THE GENERATION OF AMYLOID PRECURSOR FRAGMENTS IN GELSOLIN-RELATED AMYLOIDOSIS

Gelsolin-related amyloidosis or familial amyloidosis, Finnish type (FA F) (OMIM No105120) is a hereditary amyloid disease caused by a mutatio n in a precursor protein for amyloid (gelsolin) and characterized by c orneal dystrophy and polyneuropathy. In vitro expression of the FAF-mu tant (Asp(187) --> Asn/Tyr) secretory gelsolin in COS cells leads to g eneration of an aberrant polypeptide presumably representing the precu rsor 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 Cys(188)-Cys(201) disulfide bond, norm ally formed next to the FAF mutation site. We compared cells of differ ent tissue origin and discovered a dramatic difference between the amo unt of cleavage of FAF gelsolin to the amyloid precursor in neuronal a nd non-neuronal cells. More than half of the mutant gelsolin was cleav ed in PC12 and in vitro differentiated human neuronal progenitor cells . In contrast, human fibroblasts and Schwannoma cell cultures showed o nly a limited capacity to cleave FAF gelsolin, although the cleavage m echanism per se seems to be similar in the various cell types, The pre sent findings of processing and distribution of secreted FAF gelsolin in the neuronal cells emphasize the role of neurons in the tissue path ogenesis of this amyloid polyneuropathy.