Mitochondrial dysfunction induced by a post-translationally modified amyloid linked to a familial mutation in an alternative model of neurodegeneration

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1842

Article

Todd, Krysti¹  Fossati, Silvia¹  Ghiso, Jorge^1,2  Rostagno, Agueda¹ 

[1] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[2] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA

关键词: Familial British dementia;    Cerebral amyloidosis;    Oligomeric amyloid assemblies;    Apoptosis;    Cytochrome c;    Oxidative stress;   

DOI  :  10.1016/j.bbadis.2014.09.010

来源: Elsevier

【 摘 要 】

Familial British dementia (FBD) is an early-onset non-amyloid-beta (A beta) 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 A beta 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. (C) 2014 Elsevier B.V. All rights reserved.

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