Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia

Seong Hun Kim, Rong Wang, David J. Gordon, Joseph Bass, Donald F. Steiner, David G. Lynn, Gopal Thinakaran, Stephen C. Meredith, Sangram S. Sisodia*

*Corresponding author for this work

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

The genetic lesion underlying familial British dementia (FBD), an autosomal dominant neurodegenerative disorder, is a T-A transversion at the termination codon of the BRI gene. The mutant gene encodes BRI-L, the precursor of ABri peptides that accumulate in amyloid deposits in FBD brain. We now report that both BRI-L and its wild-type counterpart, BRI, were constitutively processed by the proprotein convertase, furin, resulting in the secretion of carboxyl-terminal peptides that encompass all or part of ABri. Elevated levels of peptides were generated from the mutant BRI precursor. Electron microscopic studies revealed that synthetic ABri peptides assembled into irregular, short fibrils. Collectively, our results support the view that enhanced furin-mediated processing of mutant BRI generates fibrillogenic peptides that initiate the pathogenesis of FBD.

Original languageEnglish (US)
Pages (from-to)984-988
Number of pages5
JournalNature Neuroscience
Volume2
Issue number11
DOIs
StatePublished - Nov 1 1999

ASJC Scopus subject areas

  • Neuroscience(all)

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    Kim, S. H., Wang, R., Gordon, D. J., Bass, J., Steiner, D. F., Lynn, D. G., Thinakaran, G., Meredith, S. C., & Sisodia, S. S. (1999). Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Nature Neuroscience, 2(11), 984-988. https://doi.org/10.1038/14783