Aggregation Profiling of C9orf72 Dipeptide Repeat Proteins Transgenically Expressed in Drosophila melanogaster Using an Analytical Ultracentrifuge Equipped with Fluorescence Detection

Kokona, Bashkim; Cunningham, Nicole; Quinn, Jeanne M.; Fairman, Robert

doi:10.1007/978-1-4939-9678-0_6

Cited by 2 publications

(1 citation statement)

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“…27 The nematode C. elegans is an established model to study aging, age-associated pathology studying genetic approaches to understand the aging process, age-related diseases, mechanisms associated with changes in lifespan, impact of xenotoxicants on neuromotor function, and for preclinical screening of natural products as well as pharmacophores. 28 The nematode possesses eight dopaminergic neurons, which are tasked with locomotory function.…”

Section: Introductionmentioning

confidence: 99%

Interfacial Interactions between Nanoplastics and Biological Systems: toward an Atomic and Molecular Understanding of Plastics-Driven Biological Dyshomeostasis

Karim,

Yadav,

Sweety

et al. 2024

ACS Appl. Mater. Interfaces

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Micro- and nano-plastics (NPs) are found in human milk, blood, tissues, and organs and associate with aberrant health outcomes including inflammation, genotoxicity, developmental disorders, onset of chronic diseases, and autoimmune disorders. Yet, interfacial interactions between plastics and biomolecular systems remain underexplored. Here, we have examined experimentally, in vitro, in vivo, and by computation, the impact of polystyrene (PS) NPs on a host of biomolecular systems and assemblies. Our results reveal that PS NPs essentially abolished the helix-content of the milk protein β-lactoglobulin (BLG) in a dose-dependent manner. Helix loss is corelated with the near stoichiometric formation of β-sheet elements in the protein. Structural alterations in BLG are also likely responsible for the nanoparticle-dependent attrition in binding affinity and weaker on-rate constant of retinol, its physiological ligand (compromising its nutritional role). PS NP-driven helix-to-sheet conversion was also observed in the amyloid-forming trajectory of hen egg-white lysozyme (accelerated fibril formation and reduced helical content in fibrils). Caenorhabditis elegans exposed to PS NPs exhibited a decrease in the fluorescence of green fluorescent protein-tagged dopaminergic neurons and locomotory deficits (akin to the neurotoxin paraquat exposure). Finally, in silico analyses revealed that the most favorable PS/BLG docking score and binding energies corresponded to a pose near the hydrophobic ligand binding pocket (calyx) of the protein where the NP fragment was found to make nonpolar contacts with side-chain residues via the hydrophobic effect and van der Waals forces, compromising side chain/retinol contacts. Binding energetics indicate that PS/BLG interactions destabilize the binding of retinol to the protein and can potentially displace retinol from the calyx region of BLG, thereby impairing its biological function. Collectively, the experimental and high-resolution in silico data provide new insights into the mechanism(s) by which PS NPs corrupt the bimolecular structure and function, induce amyloidosis and onset neuronal injury, and drive aberrant physiological and behavioral outcomes.

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Section: Introductionmentioning

confidence: 99%