Biology subjects

Maghsoodi, F.

Publications and source records attributed to Maghsoodi, F..

2 recordsLinked to original sources

bioRxiv2022

Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-oxidation: A Molecular Dynamic Simulation Study

Selective photosensitized oxidation of amyloid protein aggregates is being investigated as a possible therapeutic strategy for treating Alzheimers disease (AD). Photo-oxidation has been shown to lead to the degradation of amyloid-{beta} (A{beta}) aggregates, ameliorate aggregate toxicity and reduce aggregate levels in the brains of AD animal models. To shed light on the mechanism by which photo-oxidation induces fibril destabilization, we carried out an all-atom molecular dynamics (MD) simulation to examine the effect of methionine (Met35) oxidation on the conformation and stability of a highly {beta}-sheet-rich A{beta}9-40 protofibril composed of 12 monomers. Analyses of up to 1 s MD simulations showed that the oxidation of the Met35 residues reduced the overall conformational stability of the protofibril. Specifically, Met35 oxidation that resulted in the addition of hydrophilic oxygens disrupted the hydrophobic interface that stabilizes the stacking of the two hexamers that composed the protofibril. The oxidized protofibril is more solvent exposed, less compact, and exhibits more backbone flexibility. However, it retained the underlying U-shaped architecture of each peptide. Although some loss of {beta}-sheets occurred, a significant portion (~76%) remained. twisting of the peptides along the protofibril axis was observed, and the hexamers remained. Our simulation results are thus consistent with our experimental observation that photo-oxidation of A{beta}40 fibrils results in the dis-agglomeration and fragmentation of A{beta} fibrils, but did not cause complete disruption of the fibrillar morphology or {beta}-sheet structures. The partial destabilization of A{beta} aggregates supports the further development of photosensitized platforms for the selective targeting and clearance of A{beta} aggregates as a therapeutic strategy for treating AD.

bioengineering↗

bioRxiv2021

Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimers disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylene-based compounds (OPEs) exhibit selective binding and fluorescence turn-on in the presence of pre-fibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-{beta} (A{beta}) and -synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of toxic A{beta} aggregates and compared its efficacy to the well-known but non-selective photosensitizer methylene blue (MB). Our results show that while MB photo-oxidized both monomeric and fibrillar conformers of A{beta}40, OPE oxidized only A{beta}40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed, but retained the characteristic {beta}-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPEs photosensitizing activity overcomes the limitation of off-target oxidation of currently available photosensitizers, and represents a significant advancement of PDT as a viable strategy to treat neurodegenerative disorders.

neuroscience↗