cytochrome-c-t and Amyloid-Neuropathies--Familial

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.

Topics: Adaptor Proteins, Signal Transducing; Amyloid; Amyloid Neuropathies, Familial; Apoptosis; Blotting, Western; Cell Line, Tumor; Cerebral Amyloid Angiopathy, Familial; Circular Dichroism; Codon, Terminator; Cytochromes c; Humans; Membrane Glycoproteins; Membrane Potential, Mitochondrial; Microscopy, Confocal; Mitochondria; Models, Neurological; Mutation; Neurodegenerative Diseases; Peptides; Protein Isoforms; Protein Processing, Post-Translational; Pyrrolidonecarboxylic Acid