First evidence for helical transitions in supercoiled DNA by amyloid Beta Peptide (1-42) and aluminum: a new insight in understanding Alzheimer's disease.
Previously, we evidenced a B --> Z helical change in Alzheimer's brain genomic DNA, leading to a hypothesis that Alzheimer's disease (AD) etiological factors such as aluminum (Al), amyloid beta (Abeta) peptide, and Tau might play a role in modulating DNA topology. In the present study, we investigated the interaction of Al and Abeta with DNA. Our results show that Abeta(1-42) could induce a B --> Psi (Psi) conformational change in pUC 18 supercoiled DNA (scDNA), Abeta(1-16) caused an altered B-form, whereas Al induced a complex B-C-A mixed conformation. Ethidium bromide binding and agarose gel electrophoresis studies revealed that Al uncoiled the DNAto a fully relaxed form, whereas Abeta(1-42) and Abeta(1-16) effected a partial uncoiling and also showed differential sensitivity toward chloroquine-induced topoisomer separation. Our findings show for the first time that Abeta and Al modulate both helicity and superhelicity in scDNA. A new hypothetical model explaining the potential toxicity of Abeta and Al in terms of their DNA binding properties leading to DNA conformational alteration is proposed.
Hegde
Muralidhar L
ML
Department of Biochemistry and Nutrition, Central Food Technological Research Institute, Mysore-570013, India.
Anitha
Suram
S
Latha
Kallur S
KS
Mustak
Mohammed S
MS
Stein
Reuven
R
Ravid
Rivka
R
Rao
K S Jagannatha
KS
D000368:Aged; D000535:Aluminum / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002738:Chloroquine / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D026942:DNA Topoisomerases / Q000187:drug effects / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry* / Q000187:drug effects; D043542:DNA, Z-Form / Q000737:chemistry / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004996:Ethidium; D005260:Female; D005708:Gallium / Q000737:chemistry / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D004278:DNA, Superhelical; D043542:DNA, Z-Form; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C034163:gallium chloride; D002738:Chloroquine; D004247:DNA; D005708:Gallium; D000535:Aluminum; D026942:DNA Topoisomerases; D004996:Ethidium