title: The Familial British Dementia Mutation Promotes Formation of Neurotoxic Cystine Cross-linked Amyloid Bri (ABri) Oligomers.
abstract: Familial British dementia (FBD) is an inherited neurodegenerative disease believed to result from a mutation in the BRI2 gene. Post-translational processing of wild type BRI2 and FBD-BRI2 result in the production of a 23-residue long Bri peptide and a 34-amino acid long ABri peptide, respectively, and ABri is found deposited in the brains of individuals with FBD. Similarities in the neuropathology and clinical presentation shared by FBD and Alzheimer disease (AD) have led some to suggest that ABri and the AD-associated amyloid β-protein (Aβ) are molecular equivalents that trigger analogous pathogenic cascades. But the sequences and innate properties of ABri and Aβ are quite different, notably ABri contains two cysteine residues that can form disulfide bonds. Thus we sought to determine whether ABri was neurotoxic and if this activity was regulated by oxidation and/or aggregation. Crucially, the type of oxidative cross-linking dramatically influenced both ABri aggregation and toxicity. Cyclization of Bri and ABri resulted in production of biologically inert monomers that showed no propensity to assemble, whereas reduced ABri and reduced Bri aggregated forming thioflavin T-positive amyloid fibrils that lacked significant toxic activity. ABri was more prone to form inter-molecular disulfide bonds than Bri and the formation of covalently stabilized ABri oligomers was associated with toxicity. These results suggest that extension of the C-terminal of Bri causes a shift in the type of disulfide bonds formed and that structures built from covalently cross-linked oligomers can interact with neurons and compromise their function and viability.
authors.affiliation: From the Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Republic of Ireland and the Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Adam
authors.initials: A
authors.lastname: Cantlon
authors.affiliation: From the Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Republic of Ireland and.
authors.forename: Carlo Sala
authors.initials: CS
authors.lastname: Frigerio
authors.affiliation: From the Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Republic of Ireland and.
authors.forename: Darragh B
authors.initials: DB
authors.lastname: Freir
authors.affiliation: From the Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Republic of Ireland and.
authors.forename: Barry
authors.initials: B
authors.lastname: Boland
authors.affiliation: the Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Ming
authors.initials: M
authors.lastname: Jin
authors.affiliation: the Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 dwalsh3@partners.org.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D028227:Amyloid Neuropathies, Familial; D000818:Animals; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D003553:Cystine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009498:Neurotoxins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D009498:Neurotoxins; D003553:Cystine
keywords: ABri; aggregation; amyloid; neurodegenerative disease; oxidation; protein misfolding; synaptic plasticity; toxicity