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

The genetic lesion underlying familial British dementia (FBD), an autosomal dominant neurodegenerative disorder, is a T-A transversion at the terminat ion 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 repo rt that both BRI-L and its wild-type counterpart, BRI, were constitutively processed by the proprotein convertase, furin, resulting in the secretion o f carboxyl-terminal peptides that encompass all or part of ABri. Elevated l evels of peptides were generated from the mutant BRI precursor. Electron mi croscopic studies revealed that synthetic ABri peptides assembled into irre gular, short fibrils. Collectively, our results support the view that enhan ced furin-mediated processing of mutant BRI generates fibrillogenic peptide s that initiate the pathogenesis of FBD.