Aggregation of irisin and its prevention by trehalose: A biophysical approach

Waseem, Rashid; Yameen, Daraksha; Khan, Tanzeel; Anwer, Ayesha; Kazim, Syed Naqui; Haque, Mohammad Mahfuzul; Hassan, Md. Imtaiyaz; Islam, Asimul

doi:10.1016/j.molstruc.2023.135078

Cited by 8 publications

(3 citation statements)

References 65 publications

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“…observed at the final plateau line, b denotes a constant value that remains unaffected by time at a given wavelength, A 0 represents the F.I of the initial baseline and osmolyte concentration, and T agg refers to the time of 50% of maximum F.I. T lag was calculated by putting the value of T agg in ( T agg – 2 b ) …”

Section: Methodsmentioning

confidence: 99%

“…The inhibition of α-Syn aggregation is considered a promising therapeutic strategy for PD and several other synucleinopathies disorders that are leading causes of dementia worldwide. Protein aggregates can be identified prior to the onset of clinical symptoms in neurodegenerative conditions, making protein aggregation/fibrillation an ideal focus for the development of therapeutic interventions and investigation approaches . Several approaches, such as peptides, small molecules such as tannic acid, curcumin, ellagic acid, resveratrol, and osmolytes like trehalose, and sorbitol, have been used to inhibit α-Syn aggregation and stabilize the protein in its monomeric form. − There is presently no preventive treatment in the market, even though several compounds have been identified in the literature for stabilizing the normal conformation of α-Syn, preventing its aggregation, or dissolving aggregated α-Syn.…”

Section: Introductionmentioning

confidence: 99%

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Understanding the Modulation of α-Synuclein Fibrillation by N-Acetyl Aspartate: A Brain Metabolite

Khan,

Waseem,

Shahid

et al. 2024

ACS Omega

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α-Synuclein (α-Syn) fibrillation is a prominent contributor to neuronal deterioration and plays a significant role in the advancement of Parkinson's Disease (PD). Considering this, the exploration of novel compounds that can inhibit or modulate the aggregation of α-Syn is a topic of significant research. This study, for the first time, elucidated the effect of N-acetyl aspartate (NAA), a brain osmolyte, on α-Syn aggregation using spectroscopic and microscopic approaches. Thioflavin T (ThT) assay revealed that a lower concentration of NAA inhibits α-Syn aggregation, whereas higher concentrations of NAA accelerate the aggregation. Further, this paradoxical effect of NAA was complemented by ANS, RLS, and the turbidity assay. The secondary structure transition was more pronounced at higher concentrations of NAA by circular dichroism, corroborating the fluorescence spectroscopic observations. Confocal microscopy also confirmed the paradoxical effect of NAA on α-Syn aggregation. Interaction studies including fluorescence quenching and molecular docking were employed to determine the binding affinity and critical residues involved in the α-Syn-NAA interaction. The explanation for this paradoxical nature of NAA could be a solvophobic effect. The results offer a profound understanding of the modulatory mechanism of α-Syn aggregation by NAA, thereby suggesting the potential role of NAA at lower concentrations in therapeutics against α-Syn aggregation-related disorders.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Understanding the Modulation of α-Synuclein Fibrillation by N-Acetyl Aspartate: A Brain Metabolite

Khan,

Waseem,

Shahid

et al. 2024

ACS Omega

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“…To recreate the crowded environment found within living cells, researchers have used crowding agents in many studies. − These agents act as inert cosolutes, occupying significant volumes in the system without interacting with macromolecules that undergo LLPS to form MLOs. Crowding agents can be classified into two categories: molecular crowders and macromolecular crowders, based on their differences in molecule size, shape, flexibility, and occupied volume. , Small molecules such as sucrose, trehalose, sorbitol, and glycerol have been studied as molecular crowders to improve the catalytic efficiency of enzymes and stabilize protein molecules against thermal stress. − Macromolecules such as polyethylene glycol (PEG), ficoll, and dextran are also widely used to mimic the crowded environment within cells. ,− The physical properties of molecular and macromolecular crowders differ, leading us to hypothesize that they could have different impacts on the behavior of charged macromolecules and thus the phase behavior of macromolecular complexes. Therefore, this study aims to investigate the effects of molecular and macromolecular crowding agents on the interaction mechanism as well as the mesoscale structure of a model protein–polymer complex coacervate system.…”

Section: Introductionmentioning

confidence: 99%

Understanding the Impacts of Molecular and Macromolecular Crowding Agents on Protein–Polymer Complex Coacervates

Biswas,

Hecht,

Noble

et al. 2023

Biomacromolecules

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Complex coacervation refers to the liquid–liquid phase separation (LLPS) process occurring between charged macromolecules. The study of complex coacervation is of great interest due to its implications in the formation of membraneless organelles (MLOs) in living cells. However, the impacts of the crowded intracellular environment on the behavior and interactions of biomolecules involved in MLO formation are not fully understood. To address this knowledge gap, we investigated the effects of crowding on a model protein–polymer complex coacervate system. Specifically, we examined the influence of sucrose as a molecular crowder and polyethylene glycol (PEG) as a macromolecular crowder. Our results reveal that the presence of crowders led to the formation of larger coacervate droplets that remained stable over a 25-day period. While sucrose had a minimal effect on the physical properties of the coacervates, PEG led to the formation of coacervates with distinct characteristics, including higher density, increased protein and polymer content, and a more compact internal structure. These differences in coacervate properties can be attributed to the effects of crowders on individual macromolecules, such as the conformation of model polymers, and nonspecific interactions among model protein molecules. Moreover, our results show that sucrose and PEG have different partition behaviors: sucrose was present in both the coacervate and dilute phases, while PEG was observed to be excluded from the coacervate phase. Collectively, our findings provide insights into the understanding of crowding effects on complex coacervation, shedding light on the formation and properties of coacervates in the context of MLOs.

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