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A more recent version of this article appeared on January 11, 2002
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M108739200v1
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Papers In Press, published online ahead of print November 14, 2001
J. Biol. Chem, 10.1074/jbc.M108739200
Submitted on September 11, 2001
Revised on November 6, 2001
Accepted on November 14, 2001

Proteolytic processing of familial British dementia associated BRI variants: Evidence for enhanced intracellular accumulation of amyloidogenic peptides

Seong-Hun Kim, John Creemers, Su Chu, Gopal Thinakaran, and Sangram S Sisodia

Neurobiology, Pharmacology & Physiology, University of Chicago, Chicago, IL 60637

Corresponding Author: ssisodia{at}drugs.bsd.uchicago.edu

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 a1-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 & LPC show much lower activities. Interestingly, LPC also exhibits enhanced cleavage of BRI-L compared to 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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