Familial British dementia (FBD), a rare autosomal dominant neurodegenerative disorder, shares features with Alzheimer's disease, including amyloid plaque deposits, neurofibrillary tangles, neuronal loss, progressive dementia, but clinically presents with additional physical defects [1,2]. A mutation in the termination codon of the BRI gene produces a BRI precursor protein 11 amino acids longer than the wild-type protein [3,4]. Mutant and wild-type precursor proteins both may undergo furin cleavage between residues 243 and 244, producing a peptide of 34 amino acids in the case of ABri and 23 amino acids long in the case of the wild type peptide. The ABri 4kDa peptide is the main component of the amyloid deposits found in familial British dementia brains. A decamer duplication in the 3′ region of the BRI gene originates the peptide Adan that is associated with dementia in Familial Danish dementia (FDD), similar to FBD clinically, but with additional hearing and eyesight loss . The resulting reading frame is extended to 277 amino acid residues, and cleavage by furin releases a peptide of 34 residues, which is identical to Abri and WT in its N-terminal 22-residues, but contains a distinct C-terminal 10 residues composed of mainly hydrophobic residues. Here we demonstrate that C-terminal extensions of Abri and Adan are required to elongate initially-formed dimers to neurotoxic soluble oligomers and fibrils. In contrast, the shorter wild-type peptide does not aggregate under the same conditions and is not toxic. Conformational analyses indicate triple-β-sheet structures. Soluble nonfibrillar oligomers of oxidised ABri and reduced Adan were observed in solution (pH7.4) of peptides prior to the appearance of mature fibrils.
ASJC Scopus subject areas
- Structural Biology