title: Mitochondrial dysfunction induced by a post-translationally modified amyloid linked to a familial mutation in an alternative model of neurodegeneration.
abstract: Familial British dementia (FBD) is an early-onset non-amyloid-β (Aβ) cerebral amyloidosis that presents with severe cognitive decline and strikingly similar neuropathological features to those present in Alzheimer's disease (AD). FBD is associated with a T to A single nucleotide transition in the stop codon of a gene encoding BRI2, leading to the production of an elongated precursor protein. Furin-like proteolytic processing at its C-terminus releases a longer-than-normal 34 amino acid peptide, ABri, exhibiting amyloidogenic properties not seen in its 23 amino acid physiologic counterpart Bri1-23. Deposited ABri exhibits abundant post-translational pyroglutamate (pE) formation at the N-terminus, a feature seen in truncated forms of Aβ found in AD deposits, and co-exists with neurofibrillary tangles almost identical to those found in AD. We tested the impact of the FBD mutation alone and in conjunction with the pE post-translational modification on the structural properties and associated neurotoxicity of the ABri peptide. The presence of pE conferred to the ABri molecule enhanced hydrophobicity and accelerated aggregation/fibrillization properties. ABri pE was capable of triggering oxidative stress, loss of mitochondrial membrane potential and activation of caspase-mediated apoptotic mechanisms in neuronal cells, whereas homologous peptides lacking the elongated C-terminus and/or the N-terminal pE were unable to induce similar detrimental cellular pathways. The data indicate that the presence of N-terminal pE is not in itself sufficient to induce pathogenic changes in the physiologic Bri1-23 peptides but that its combination with the ABri mutation is critical for the molecular pathogenesis of FBD.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Krysti
authors.initials: K
authors.lastname: Todd
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fossati
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address: jorge.ghiso@nyumc.org.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: agueda.rostagno@nyumc.org.
authors.forename: Agueda
authors.initials: A
authors.lastname: Rostagno
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D028227:Amyloid Neuropathies, Familial; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics* / Q000378:metabolism; D002942:Circular Dichroism; D018388:Codon, Terminator / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D008959:Models, Neurological; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D018388:Codon, Terminator; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D010455:Peptides; D020033:Protein Isoforms; D045304:Cytochromes c; D011761:Pyrrolidonecarboxylic Acid
keywords: Apoptosis; Cerebral amyloidosis; Cytochrome c; Familial British dementia; Oligomeric amyloid assemblies; Oxidative stress