Abstract
Different mutations in the BRI(2) 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 alpha1-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.
Highlights
Different mutations in the BRI2 gene cause rare neurodegenerative conditions, termed familial British dementia (FBD) and familial Danish dementia (FDD)
We previously demonstrated that BRI is a type II integral membrane protein and that both wild type BRI and the FBDassociated mutant BRI-L, are processed by furin between amino acids 243 and 244, resulting in the production of Cterminal ϳ3 kDa wild type and ϳ4 kDa ABri peptides, respectively, which are released into the conditioned medium [8]
Recent studies revealed that a mutation at the termination codon of the BRI2 gene encoding a type II membrane protein, BRI, is the underlying genetic defect of FBD, an autosomal dominant neurodegenerative disorder [2]
Summary
A 34amino acid peptide, termed ABri, generated by endoproteolytic processing of this mutant precursor protein is deposited in the brains of FBD patients [2, 6]. The BRI2 mutation in FDD is the presence of a 10-nucleotide (TTTAATTTGT) duplication between codons 265 and 266, just prior to the normal termination codon This decamer duplication leads to the loss of serine 266 and a change in the reading frame to generate an 11-amino acid longer protein (BRI-D) that has a unique C-terminal sequence. We previously demonstrated that BRI is a type II integral membrane protein and that both wild type BRI and the FBDassociated mutant BRI-L, are processed by furin between amino acids 243 and 244, resulting in the production of Cterminal ϳ3 kDa wild type and ϳ4 kDa ABri peptides, respectively, which are released into the conditioned medium [8]. While the ABri peptide is detected both intracellularly and in the medium of transfected cells, the ADan peptide accumulates predominantly in intracellular compartments
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