Zinc-Mediated Binding of Nucleic Acids to Amyloid-β Aggregates: Role of Histidine Residues

Abstract

Amyloid-β peptide (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis. Besides extracellular Aβ, intraneuronal Aβ (iAβ) has been suggested to contribute to AD onset and development. Based on reported in vitro Aβ-DNA interactions and nuclear localization of iAβ, the interference of iAβ with the normal DNA expression has recently been proposed as a plausible pathway by which Aβ can exert neurotoxicity. Employing the sedimentation assay, thioflavin T fluorescence, and dynamic light scattering we have studied effects of zinc ions on binding of RNA and single- and double-stranded DNA molecules to Aβ42 aggregates. It has been found that zinc ions significantly enhance the binding of RNA and DNA molecules to pre-formed β-sheet rich Aβ42 aggregates. Another type of Aβ42 aggregates, the zinc-induced amorphous aggregates, was demonstrated to also bind all types of nucleic acids tested. To evaluate the role of the Aβ metal-binding domain's histidine residues in Aβ-nucleic acid interactions mediated by zinc, Aβ16 mutants with substitutions H6R and H6A-H13A and rat Aβ16 lacking histidine residue 13 were used. The zinc-induced interaction of Aβ16 with DNA was shown to critically depend on histidine residues 6 and 13. However, the inclusion of H6R mutation in Aβ42 peptide did not affect DNA binding to Aβ42 aggregates. Since oxidative and/or nitrosative stresses implicated in AD pathogenesis are known to release zinc ions from metallothioneins in cytoplasm and cell nuclei, our findings suggest that intracellular zinc can be an important player in iAβ-nucleic acid interactions.

The English (H6R) Mutation of the Alzheimer’s Disease Amyloid-β Peptide Modulates Its Zinc-Induced Aggregation

“…DLS measurements were carried out on a Zetasizer Nano ZS apparatus (Malvern Instruments Ltd., Malvern, UK) at 25 °C as described elsewhere [ 18 , 23 ]. The apparatus is able to measure particles sizes in the range of 0.6 nm to 10 µm.…”

“…The double substitution—R5 and H6 with alanine residues—was also found to have no impact on the Zn 2+ -triggered “coil-to-β-sheet” conformational transition in Aβ28 and Aβ40 peptides [ 15 ]. However, as we have earlier shown, the substitution of H6 with arginine residue (H6R, known as the “English mutation” associated with the early onset of AD [ 17 ]), while not preventing the Zn 2+ -induced Aβ42 aggregation, resulted nonetheless in some reduction of the number of sedimentation-prone Zn 2+ -induced aggregates (at Zn 2+ /peptide ratios of 1 to 3), compared to the wild-type Aβ42 [ 18 ]. Aβ42 peptides bearing the H6R mutation (H6R-Aβ42) were also shown to produce Zn 2+ -induced aggregates of a smaller size at a Zn 2+ /peptide ratio below 1 [ 19 ].…”

Amyloid plaques beyond Aβ: a survey of the diverse modulators of amyloid aggregation

“…1 ), may change conformation in response to Zn 2+ ions, indicating that the binding interaction has global implications for Aβ structure (Rezaei-Ghaleh et al 2011 ). Additionally, Zn 2+ has been shown to promote nucleic acid association with Aβ42, with particular importance for histidine residues 6 and 13 (Khmeleva et al 2016 ). Zn 2+ has also been shown to play a protective role in ROS generation, by competing for Aβ40/42 fibril binding with Cu 2+ (low μM/high pM for Cu 2+ vs. low- to mid-μM for Zn 2+ dissociation constants) (Faller and Hureau 2009 ).…”

Could Amyloid-β 1–42 or α-Synuclein Interact Directly with Mitochondrial DNA? A Hypothesis

“…27 Recently, a study indicated that Aβ1−42 could bind to DNA from its N-terminal region. 28 Besides, critical research showed that Aβ1−42 could bind to promoter regions of specific genes that induce its production through an interacting domain. 11,29 Our previous study also demonstrated the alterations in the expression of neurodegeneration-related genes due to Aβ1−42 presence.…”

“…Khmeleva et al showed that zinc ions significantly enhance the binding of RNA and DNA molecules to Aβ1−42 aggregates. 28 It is speculated that the binding of the zinc ions to Aβ aggregates can cause it to acquire a trait like the zinc finger transcription factors. In a study conducted in 2016, it was shown that Aβ16 (the region of Aβ that interacts with metals) could interact with RNA by using synthetic, randomly generated DNA and RNA molecules.…”