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: Krysti Todd, Silvia Fossati, Jorge Ghiso, Agueda Rostagno
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1842 Issue 12 Pt A Pg. 2457-67 (Dec 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25261792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Amyloid
• Codon, Terminator
• ITM2B protein, human
• Membrane Glycoproteins
• Peptides
• Protein Isoforms
• Cytochromes c
• Pyrrolidonecarboxylic Acid

Topics

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