ABSTRACT
Familial Danish Dementia (FDD) is an autosomal disease, which is distinguished by gradual loss of vision, deafness, progressive ataxia and dementia. Cataract is the first manifestation of the disease. In this article, we demonstrate a specific correlation between the poisoning of the chaperone activity of the rat eye lens alpha-crystallins, loss of lens transparency in organ culture by the pathogenic form of the Danish dementia peptide, i.e. the reduced Danish dementia peptide (redADan peptide), by a combination of ex vivo, in vitro, biophysical and biochemical techniques. The interaction of redADan peptide and lens crystallins are very specific when compared with another chaperone, HSP-70, underscoring the specificity of the pathogenic form of Danish dementia peptide, redADan, for the early onset of cataract in this disease.
Subject(s)
Cataract/complications , Dementia/complications , Lens, Crystalline/pathology , alpha-Crystallins/physiology , Adaptor Proteins, Signal Transducing , Aging , Amyloid beta-Peptides/toxicity , Animals , Ataxia/complications , Disease Models, Animal , Humans , Membrane Glycoproteins , Membrane Proteins/toxicity , Molecular Chaperones/physiology , Neurodegenerative Diseases/epidemiology , Rats , Vision Disorders/complicationsABSTRACT
Familial Danish dementia (FDD) is a neurodegenerative disease which results due to alterations in the BRI2 gene. The pathological symptoms of the disease are cerebral amyloidolysis, parenchymal protein deposits and neuronal degeneration. The ADan peptide is a 34 amino acid long peptide which is thought to be the major cause of amyloid deposition in brains of patients suffering from FDD. Due to the presence of two cysteine residues viz. cys5 and cys23, this peptide exists in two forms: a cyclic oxidized form where the two cysteines form a disulfide bridge and a linear reduced form where the sulphydryl groups of cysteine are free. The relationship between toxicity and structure of the reduced and oxidized forms of ADan peptides has been elucidated by a combination of biophysical and cellular toxicity assays. It is observed that the reduced peptide has a stronger lethal effect on neuronal cell lines compared to its oxidized counterparts at all stages of aggregation. Further, it is observed that the fresh reduced peptide induced greater cell death as compared to its aged counterpart.
Subject(s)
Amyloid/toxicity , Dementia/metabolism , Neurodegenerative Diseases/metabolism , Neurons/drug effects , Adaptor Proteins, Signal Transducing , Amyloid/chemistry , Amyloid/metabolism , Cell Line , Cysteine/chemistry , Humans , Membrane Glycoproteins , Membrane Proteins , Microscopy, Atomic Force , Oxidation-Reduction , Peptides, Cyclic/chemistry , Peptides, Cyclic/metabolism , Peptides, Cyclic/toxicity , Protein Conformation , Spectroscopy, Fourier Transform InfraredABSTRACT
In this study, biphenyl ethers of diverse functionality were used to assess their effect on fibrillogenesis of both the oxidized and reduced ADan peptides, in vitro. It was noted that these compounds not only stalled fibrillogenesis but were also able to disrupt pre-formed fibers. The EC(50) values for the inhibition of this process lie in the nanomolar range for 50 microM of peptide concentration, indicating the high potency of these compounds as inhibitors. It was found that these compounds impart to the peptides, an alpha-helical conformation which does not allow them to aggregate and form fibrils. These studies also point out that the transition of peptides through alpha-helical conformation may be a prelude to the onset of fibrillogenesis for oxADan peptides.
