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

Nature Neuroscience volume 2, pages 984–988 (1999)Cite this article

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.

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Figure 1: Topology and processing of BRI in mammalian cells.
Figure 2: Furin is required for BRI processing.
Figure 3: Enhanced processing of BRI-L by furin.
Figure 4: Electron micrographs of ABri and Aβ1–40 peptides.

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Acknowledgements

The authors thank Anthony A. Lanahan and Paul F. Worley for pRK5 vector, Steve Duguay for the pCMV-furin construct and Thomas Moehring for RPE.40 cells. The authors also thank Takeshi Iwatsubo (University of Tokyo) for discussions. This study was supported by National Institute of Health Grants AG14248 (S.S.S.) and 5 T32 GM07281 (D.J.G.), The Alzheimer's Association (S.M., IIRG # 98 134 and R.W.) and The Stasia Borsuk Memorial Fund (R.W.; RG1-96-070).

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Authors and Affiliations

  1. Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, Abbott 316, 947 East 58th Street, Chicago, 60637, Illinois, USA

    Seong-Hun Kim, Gopal Thinakaran & Sangram S. Sisodia

  2. Laboratory of Mass Spectrometry, Rockefeller University, New York, 10021, New York, USA

    Rong Wang

  3. Medical Scientists Training Program and Department of Biochemistry and Molecular Biology, The University of Chicago, Abbott 316, 947 East 58th Street, Chicago, 60637, Illinois, USA

    David J. Gordon

  4. Howard Hughes Medical Institute, The University of Chicago, Abbott 316, 947 East 58th Street, Chicago, 60637, Illinois, USA

    Joseph Bass & Donald F. Steiner

  5. Department of Pathology, The University of Chicago, Abbott 316, 947 East 58th Street, Chicago, 60637, Illinois, USA

    Stephen C. Meredith

  6. Department of Chemistry, The University of Chicago, Abbott 316, 947 East 58th Street, Chicago, 60637, Illinois, USA

    David G. Lynn

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  1. Seong-Hun Kim
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Correspondence to Sangram S. Sisodia.

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Kim, SH., Wang, R., Gordon, D. et al. Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Nat Neurosci 2, 984–988 (1999). https://doi.org/10.1038/14783

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