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J. Biol. Chem., Vol. 277, Issue 3, 1872-1877, January 18, 2002

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Proteolytic Processing of Familial British Dementia-associated BRI Variants
EVIDENCE FOR ENHANCED INTRACELLULAR ACCUMULATION OF AMYLOIDOGENIC PEPTIDES^*

Seong-Hun Kim, John W. M. Creemers^§, Su Chu, Gopal Thinakaran, and Sangram S. Sisodia^¶

From the  Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, Illinois 60637 and the ^§ Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, 3000 Leuven, Belgium

Different mutations in the BRI₂ gene cause rare neurodegenerative conditions, termed familial British dementia (FBD) and familial Danish dementia (FDD). The mutant genes encode BRI-L and BRI-D, the precursors of fibrillogenic ABri and ADan peptides, respectively. We previously reported that furin processes both BRI-L and its wild type counterpart, BRI, resulting in the secretion of C-terminal peptides; elevated levels of peptides were generated from BRI-L. In the present study, we show that inducible expression of 1-antitrypsin Portland, a furin inhibitor, inhibits the endoproteolysis of BRI and BRI-L in a dose-dependent manner. Moreover, comparison of the activities of several proprotein convertases reveals that furin is most efficient in endoproteolysis of BRI and BRI-L; PACE4, PC6A, PC6B, and LPC show much lower activities. Interestingly, LPC also exhibits enhanced cleavage of BRI-L compared with BRI. Finally, we demonstrate that BRI-D is also processed by furin and, like BRI-L, the cleavage of BRI-D is more efficient than that of BRI. Interestingly, while the ABri peptide is detected both intracellularly and in the medium, the ADan peptide accumulates predominantly in intracellular compartments. We propose that intracellular accumulation of amyloidogenic ADan or ABri peptides results in the neuronal damage leading to FDD and FBD, respectively.

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