Molecular Aspects of Insulin Aggregation and Various Therapeutic Interventions

Das, Anirban; Shah, Mosami; Saraogi, Ishu

doi:10.1021/acsbiomedchemau.1c00054

Cited by 40 publications

(37 citation statements)

References 126 publications

(253 reference statements)

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“…Further, this platform may also prove applicable to explore the impact of small-molecule inhibitors on other diseases. For example, the accumulation of α-synuclein contributes to the aggregation of islet amyloid polypeptide (IAPP), which has been linked to type 2 diabetes [ 103 , 104 ].…”

Section: Discussionmentioning

confidence: 99%

Using a Caenorhabditis elegans Parkinson’s Disease Model to Assess Disease Progression and Therapy Efficiency

et al. 2022

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Despite Parkinson’s Disease (PD) being the second most common neurodegenerative disease, treatment options are limited. Consequently, there is an urgent need to identify and screen new therapeutic compounds that slow or reverse the pathology of PD. Unfortunately, few new therapeutics are being produced, partly due to the low throughput and/or poor predictability of the currently used model organisms and in vivo screening methods. Our objective was to develop a simple and affordable platform for drug screening utilizing the nematode Caenorhabditis elegans. The effect of Levodopa, the “Gold standard” of PD treatment, was explored in nematodes expressing the disease-causing α-synuclein protein. We focused on two key hallmarks of PD: plaque formation and mobility. Exposure to Levodopa ameliorated the mobility defect in C. elegans, similar to people living with PD who take the drug. Further, long-term Levodopa exposure was not detrimental to lifespan. This C. elegans-based method was used to screen a selection of small-molecule drugs for an impact on α-synuclein aggregation and mobility, identifying several promising compounds worthy of further investigation, most notably Ambroxol. The simple methodology means it can be adopted in many labs to pre-screen candidate compounds for a positive impact on disease progression.

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Section: Discussionmentioning

confidence: 99%

Using a Caenorhabditis elegans Parkinson’s Disease Model to Assess Disease Progression and Therapy Efficiency

et al. 2022

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“…The mature form of insulin is a peptide hormone consisting of an A-chain (21 residues) and a B-chain (30 residues) held together by two inter-chain disulfide bonds (A7:B7 and A20:B19) and an intra-chain disulfide bond (A6:A11) in the A-chain. Moreover, insulin self-associates into a hexameric architecture due to a high concentration of zinc ions (Zn 2+ ) in the Golgi apparatus ( 38 ). Insulin hexamer is the storage form of insulin where Zn 2+ ions stabilize the hexamer structure.…”

Section: Introductionmentioning

confidence: 99%

Progress in Simulation Studies of Insulin Structure and Function

Gorai

Vashisth

2022

Front. Endocrinol.

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Insulin is a peptide hormone known for chiefly regulating glucose level in blood among several other metabolic processes. Insulin remains the most effective drug for treating diabetes mellitus. Insulin is synthesized in the pancreatic β-cells where it exists in a compact hexameric architecture although its biologically active form is monomeric. Insulin exhibits a sequence of conformational variations during the transition from the hexamer state to its biologically-active monomer state. The structural transitions and the mechanism of action of insulin have been investigated using several experimental and computational methods. This review primarily highlights the contributions of molecular dynamics (MD) simulations in elucidating the atomic-level details of conformational dynamics in insulin, where the structure of the hormone has been probed as a monomer, dimer, and hexamer. The effect of solvent, pH, temperature, and pressure have been probed at the microscopic scale. Given the focus of this review on the structure of the hormone, simulation studies involving interactions between the hormone and its receptor are only briefly highlighted, and studies on other related peptides (e.g., insulin-like growth factors) are not discussed. However, the review highlights conformational dynamics underlying the activities of reported insulin analogs and mimetics. The future prospects for computational methods in developing promising synthetic insulin analogs are also briefly highlighted.

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“…In addition, the presence of insulin oligomers/fibrils may induce autoimmune responses as documented for Parkinson´s patients, which suggests the involvement of insulin in Parkinson's pathogenesis (Wilhelm, et al, 2007). However, it should be noted that the aggregation of insulin has only been observed with externally administered forms of insulin, and not when it is normally produced in the human body (Das et al, 2022). In vitro insulin can be easily transferred into the amyloid state, if appropriate, typically denaturing conditions are applied (Sluzky et al, 1991;Brange et al, 1997;Nielsen et al, 2001;Malik and Roy, 2011).…”

Section: Introductionmentioning

confidence: 99%

The intriguing dose-dependent effect of selected amphiphilic compounds on insulin amyloid aggregation: Focus on a cholesterol-based detergent, Chobimalt

Šipošová

Петренко

Garcarova

et al. 2022

Front. Mol. Biosci.

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The amyloidogenic self-assembly of many peptides and proteins largely depends on external conditions. Among amyloid-prone proteins, insulin attracts attention because of its physiological and therapeutic importance. In the present work, the amyloid aggregation of insulin is studied in the presence of cholesterol-based detergent, Chobimalt. The strategy to elucidate the Chobimalt-induced effect on insulin fibrillogenesis is based on performing the concentration- and time-dependent analysis using a combination of different experimental techniques, such as ThT fluorescence assay, CD, AFM, SANS, and SAXS. While at the lowest Chobimalt concentration (0.1 µM; insulin to Chobimalt molar ratio of 1:0.004) the formation of insulin fibrils was not affected, the gradual increase of Chobimalt concentration (up to 100 µM; molar ratio of 1:4) led to a significant increase in ThT fluorescence, and the maximal ThT fluorescence was 3-4-fold higher than the control insulin fibril’s ThT fluorescence intensity. Kinetic studies confirm the dose-dependent experimental results. Depending on the concentration of Chobimalt, either (i) no effect is observed, or (ii) significantly, ∼10-times prolonged lag-phases accompanied by the substantial, ∼ 3-fold higher relative ThT fluorescence intensities at the steady-state phase are recorded. In addition, at certain concentrations of Chobimalt, changes in the elongation-phase are noticed. An increase in the Chobimalt concentrations also triggers the formation of insulin fibrils with sharply altered morphological appearance. The fibrils appear to be more flexible and wavy-like with a tendency to form circles. SANS and SAXS data also revealed the morphology changes of amyloid fibrils in the presence of Chobimalt. Amyloid aggregation requires the formation of unfolded intermediates, which subsequently generate amyloidogenic nuclei. We hypothesize that the different morphology of the formed insulin fibrils is the result of the gradual binding of Chobimalt to different binding sites on unfolded insulin. A similar explanation and the existence of such binding sites with different binding energies was shown previously for the nonionic detergent. Thus, the data also emphasize the importance of a protein partially-unfolded state which undergoes the process of fibrils formation; i.e., certain experimental conditions or the presence of additives may dramatically change not only kinetics but also the morphology of fibrillar aggregates.

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Molecular Aspects of Insulin Aggregation and Various Therapeutic Interventions

Cited by 40 publications

References 126 publications

Using a Caenorhabditis elegans Parkinson’s Disease Model to Assess Disease Progression and Therapy Efficiency

Using a Caenorhabditis elegans Parkinson’s Disease Model to Assess Disease Progression and Therapy Efficiency

Progress in Simulation Studies of Insulin Structure and Function

The intriguing dose-dependent effect of selected amphiphilic compounds on insulin amyloid aggregation: Focus on a cholesterol-based detergent, Chobimalt

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