Axonal transport of British and Danish amyloid peptides via secretory vesicles.
The ABri and ADan amyloid peptides deposited in familial British and Danish neurodegenerative disorders are generated by processing mutant forms of the precursor protein BRI2. Although the pathogenic process that leads to deposition of amyloid in the brains of patients has been studied extensively, the cellular processes and normal function of the precursor protein did not receive much attention. We observed in a variety of transfected cell lines the presence of two independent proteolytic processing events. In addition to the previously described cleavage, which results in the production of carboxyl-terminal approximately 3 kDa wild-type peptide or approximately 4 kDa ABri or ADan peptides, we describe a novel amino-terminal cleavage site within BRI2. Both cleavages occur within the cis- or medial-Golgi. Following cleavage, the BRI2-derived carboxyl-terminal peptides are transported via a regulated secretory pathway into secretory vesicles in neuronal cells. Worth noting is that expression of wild-type British or Danish mutants of BRI2, in mouse neuroblastoma N2a cells that do not express endogenous BRI2, induces elongation of neurites, which suggests a role for this protein in differentiation of neuronal cells.
Choi
Seung-Il
SI
Department of Pathology, New York University School of Medicine, New York, New York, USA.
Vidal
Ruben
R
Frangione
Blas
B
Levy
Efrat
E
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D003718:Denmark; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051379:Mice; D009154:Mutation; D016501:Neurites / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D022142:Secretory Vesicles / Q000378:metabolism*; D013997:Time Factors; D006113:United Kingdom
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; C120083:ITM2B protein, human; C492300:Itm2b protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments