Nanodroplet Oligomers (NanDOs) of Aβ40

Pittman, Jay M.; Srivastava, Atul; Boughter, Christopher T.; Venkata, Bharat Somireddy; Zerweck, Jonathan; Moore, Patrick C.; Smok, Izabela; Tonelli, Marco; Sachleben, Joseph R.; Meredith, Stephen C.

doi:10.1021/acs.biochem.1c00147

Cited by 4 publications

(4 citation statements)

References 82 publications

(143 reference statements)

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“…For example, different cutoffs in the number of interprotein contacts and/or backbone hydrogen bonds can be used in the analysis of protein assemblies, and the corresponding cutoff values might be determined by probability distributions derived from simulations. Further computational and experimental studies are needed to uncover the exact relationship between oligomers and droplets, including these nanodroplets …”

Section: Relationship Between Oligomers and Dropletsmentioning

confidence: 99%

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Amyloid Aggregation and Liquid–Liquid Phase Separation from the Perspective of Phase Transitions

et al. 2023

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Amyloid aggregation describes the aberrant selfassembly of peptides into ordered fibrils characterized by cross-β spine cores and is associated with many neurodegenerative diseases and Type 2 diabetes. Oligomers, populated during the early stage of aggregation, are found to be more cytotoxic than mature fibrils. Recently, many amyloidogenic peptides have been reported to undergo liquid−liquid phase separation (LLPS)�a biological process important for the compartmentalization of biomolecules in living cells�prior to fibril formation. Understanding the relationship between LLPS and amyloid aggregation, especially the formation of oligomers, is essential for uncovering disease mechanisms and mitigating amyloid toxicity. In this Perspective, available theories and models of amyloid aggregation and LLPS are first briefly reviewed. By drawing analogies to gas, liquid, and solid phases in thermodynamics, a phase diagram of protein monomer, droplet, and fibril states separated by coexistence lines can be inferred. Due to the high free energy barrier of fibrillization kinetically delaying the formation of fibril seeds out of the droplets, a "hidden" monomer-droplet coexistence line extends into the fibril phase. Amyloid aggregation can then be described as the equilibration process from the initial "out-of-equilibrium" state of a homogeneous solution of monomers to the final equilibrium state of stable amyloid fibrils coexisting with monomers and/or droplets via the formation of metastable or stable droplets as the intermediates. The relationship between droplets and oligomers is also discussed. We suggest that the droplet formation of LLPS should be considered in future studies of amyloid aggregation, which may help to better understand the aggregation process and develop therapeutic strategies to mitigate amyloid toxicity.

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Section: Relationship Between Oligomers and Dropletsmentioning

confidence: 99%

“…Further computational and experimental studies are needed to uncover the exact relationship between oligomers and droplets, including these nanodroplets. 89…”

Section: Dropletsmentioning

confidence: 99%

Amyloid Aggregation and Liquid–Liquid Phase Separation from the Perspective of Phase Transitions

et al. 2023

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“…36 Amyloid oligomers that are highly dynamic and undergo frequent exchanges with soluble peptide monomers (i.e., the low-density liquid phase) 37 can be regarded as nanodroplets of the high-density liquid phase (HDLP). 38 At low peptide concentrations, these nanodroplets are meta-stable and transient. As the peptide concentration increases, protein condensates become stable, and more peptides are partitioned into the high-density phase.…”

Section: ■ Introductionmentioning

confidence: 99%

“…These liquid biomolecular condensates are termed membraneless organelles which play important roles in physiology and pathology, including amyloidogenesis. − LLPS can be modulated by salt concentration, temperature, and pH and driven by different interaction types such as cation-π, electrostatic attraction, and hydrophobic interactions. − Using coarse-grained (CG) computer simulations complemented with experiments, we previously showed that LLPS could describe the early aggregation of amyloid proteins over a wide range of concentrations . Amyloid oligomers that are highly dynamic and undergo frequent exchanges with soluble peptide monomers (i.e., the low-density liquid phase) can be regarded as nanodroplets of the high-density liquid phase (HDLP) . At low peptide concentrations, these nanodroplets are meta-stable and transient.…”

Section: Introductionmentioning

confidence: 99%

Modulating Nanodroplet Formation En Route to Fibrillization of Amyloid Peptides with Designed Flanking Sequences

et al. 2022

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Soluble oligomers populating early amyloid aggregation can be regarded as nanodroplets of liquid−liquid phase separation (LLPS). Amyloid peptides typically contain hydrophobic aggregation-prone regions connected by hydrophilic linkers and flanking sequences, and such a sequence hydropathy pattern drives the formation of supramolecular structures in the nanodroplets and modulates subsequent fibrillization. Here, we studied LLPS and fibrillization of coarse-grained amyloid peptides with increasing flanking sequences. Nanodroplets assumed lamellar, cylindrical micellar, and spherical micellar structures with increasing peptide hydrophilic/hydrophobic ratios, and such morphologies governed subsequent fibrillization processes. Adding glycine-serine repeats as flanking sequences to Aβ 16−22 , the amyloidogenic core of amyloid-β, our computational predictions of morphological transitions were corroborated experimentally. The uncovered inter-relationships between the peptide sequence pattern, oligomer/nanodroplet morphology, and fibrillization pathway, kinetics, and structure may contribute to our understanding of pathogenic amyloidosis in aging, facilitate future efforts ameliorating amyloidosis through peptide engineering, and aid in the design of novel amyloid-based functional nanobiomaterials and nanocomposites.

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Mass photometric detection and quantification of nanoscale α-synuclein phase separation

et al. 2023

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α-Synuclein (α-Syn) liquid-liquid phase separation (LLPS) leads to irreversible amyloid fibril formation associated with Parkinson's disease pathogenesis. Critical concentrations of α-Syn LLPS are relatively high under physiological solution conditions. Moreover, α-Syn exhibits delayed LLPS kinetics under certain conditions which deviates from the behaviour predicted by classical homogeneous nucleation theory. In the current body of work, using interferometric light scattering (iSCAT), also known as mass photometry, we experimentally probe that α-Syn can form nanoscale phase separated assemblies/clusters, containing tens to hundreds of moleculesboth above and below the critical LLPS concentration down to physiologically relevant scales. The formation of these clusters is instantaneous, even under conditions where the formation of microscopically visible droplets takes several days. However, they account for a very small volume fraction below saturation concentration. The slow growth of the nanoclusters can be attributed to a kinetic barrier which can be overcome by increasing the solution temperature to just below the droplet melting point. We provide reasons for caution in quantifying dilute phase concentrations for α-Syn LLPS samples containing nanoscale droplets-which can only be separated using ultracentrifugation. In addition, we also delineate that the presence of certain surfaces facilitates α-Syn droplet nucleation under conditions of delayed kinetics but is not a mandatory prerequisite for nanocluster formation. Taken together, our findings reveal that phase separation of α-Syn occurs at a wider range of solution conditions than predicted so far and provides an important step towards understanding α-Syn LLPS within physiological scales..

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Nanodroplet Oligomers (NanDOs) of Aβ40

Cited by 4 publications

References 82 publications

Amyloid Aggregation and Liquid–Liquid Phase Separation from the Perspective of Phase Transitions

Amyloid Aggregation and Liquid–Liquid Phase Separation from the Perspective of Phase Transitions

Modulating Nanodroplet Formation En Route to Fibrillization of Amyloid Peptides with Designed Flanking Sequences

Mass photometric detection and quantification of nanoscale α-synuclein phase separation

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