Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids

Chemical Reviews, Год журнала: 2021, Номер 121(13), С. 8285 - 8307

Опубликована: Июнь 17, 2021

This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures elucidated from various in vitro ex vivo obtained fibrils. In parallel, fibril formation has studied under highly artificial but comparatively reproducible conditions. The starts with a summary what is known speculated aggregation experiments. A partially hypothetic selection model be described that may suitable to explain why amyloid look way they do, particular, at least all so far reported high cryo-electron microscopy register, cross-β-sheet mostly consist two protofilaments twisted around each other. An intrinsic feature prion-like nature assemblies. Transferring point view situation not straightforward, hypothetic, leaves many open questions need addressed future.

Язык: Английский

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LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases

Biomolecules, Год журнала: 2024, Номер 14(3), С. 320 - 320

Опубликована: Март 8, 2024

Antimicrobial peptides (AMPs), as well host defense (HDPs), constitute the first line of part innate immune system. Humans are known to express antimicrobial precursor proteins, which further processed generate AMPs, including several types α/β defensins, histatins, and cathelicidin-derived AMPs like LL37. The broad-spectrum activity is crucial defend against infections caused by pathogenic bacteria, viruses, fungi, parasites. emergence multi-drug resistant bacteria global concern for public health. prospects targeting antibiotic-resistant strains with high significance developing new generations agents. 37-residue long LL37, only cathelicidin family AMP in humans, has been major focus past few decades research. LL37 likely underscored its expression throughout body, spanning from epithelial cells various organs—testis, skin, respiratory tract, gastrointestinal tract—to cells. Remarkably, apart canonical direct killing organisms, exerts other activities, inflammatory response modulation, chemo-attraction, wound healing closure at infected sites. In addition, derived bestowed anti-cancer anti-amyloidogenic properties. this review article, we aim develop integrative, mechanistic insight into peptides, based on biophysical, structural, functional studies recent years. We believe that will pave way future research structures, biochemical biophysical properties, design novel LL37-based molecules.

Язык: Английский

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Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Фев. 24, 2022

Human islet amyloid polypeptide (hIAPP) self-assembles into fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism assembly wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that aggregation both peptides involves primary nucleation, secondary nucleation elongation. also report discovery two structurally distinct small-molecule modulators assembly, one delaying wt hIAPP, but not S20G; while other enhances rate variants at substoichiometric concentrations. Investigation inhibition mechanism(s) using kinetics, native mass spectrometry, fluorescence titration, SPR NMR revealed inhibitor retards elongation, by binding peptide monomers. By contrast, accelerator predominantly interacts with species formed lag phase. These compounds represent useful tools may serve as promising starting-points for development therapeutics T2D.

Язык: Английский

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The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer’s diseases

Diabetology & Metabolic Syndrome, Год журнала: 2023, Номер 15(1)

Опубликована: Май 13, 2023

Abstract Human Islet amyloid polypeptide (hIAPP) from pancreatic β cells in the islet of Langerhans has different physiological functions including inhibiting release insulin and glucagon. Type 2 diabetes mellitus (T2DM) is an endocrine disorder due to relative insufficiency resistance (IR) associated with increased circulating hIAPP. Remarkably, hIAPP structural similarity beta (Aβ) can engage pathogenesis T2DM Alzheimer’s disease (AD). Therefore, present review aimed elucidate how acts as a link between AD. IR, aging low cell mass increase expression which binds membrane leading aberrant Ca 2+ activation proteolytic enzymes series events causing loss cells. Peripheral plays major role AD, high level AD risk patients. However, there no hard evidence for brain-derived Nevertheless, oxidative stress, mitochondrial dysfunction, chaperon-mediated autophagy, heparan sulfate proteoglycan (HSPG), immune response, zinc homeostasis could be possible mechanisms induction aggregation risk. In conclusion, increasing levels patients predispose them development progression Dipeptidyl peptidase 4 (DPP4) inhibitors glucagon-like peptide-1 (GLP-1) agonists attenuate by deposition hIAP.

Язык: Английский

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NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

Journal of Cellular and Molecular Medicine, Год журнала: 2023, Номер 27(13), С. 1775 - 1789

Опубликована: Май 21, 2023

Abstract Parkinson's disease (PD) is the second most common neurodegenerative after Alzheimer's (AD). Genetic predisposition and immune dysfunction are involved in pathogenesis of PD. Notably, peripheral inflammatory disorders neuroinflammation associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) due to hyperglycaemia‐induced oxidative stress release pro‐inflammatory cytokines. Particularly, insulin resistance (IR) T2DM promotes degeneration dopaminergic neurons substantia nigra (SN). Thus, T2DM‐induced predispose development progression PD, their targeting may reduce risk T2DM. Therefore, this narrative review aims find potential link between by investigating role signalling pathways, mainly nuclear factor kappa B (NF‐κB) nod‐like receptor pyrin 3 (NLRP3) inflammasome. NF‐κB implicated T2DM, activation induction neuronal apoptosis was also confirmed patients. Systemic NLRP3 inflammasome accumulation α‐synuclein SN. Increasing patients enhances interleukin (IL)‐1β followed systemic inflammation neuroinflammation. In conclusion, NF‐κB/NLRP3 axis could be causal pathway The mechanisms triggered activated lead pancreatic β‐cell attenuation changes inhibiting early future risk.

Язык: Английский

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Supersaturation, a Critical Factor Underlying Proteostasis of Amyloid Fibril Formation

Journal of Molecular Biology, Год журнала: 2024, Номер 436(14), С. 168475 - 168475

Опубликована: Фев. 3, 2024

Язык: Английский

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Molecular insights into the phase transition of lysozyme into amyloid nanostructures: Implications of therapeutic strategies in diverse pathological conditions

Advances in Colloid and Interface Science, Год журнала: 2024, Номер 331, С. 103205 - 103205

Опубликована: Май 23, 2024

Язык: Английский

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Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection

Nature Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Язык: Английский

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Molecular insight into cross-interaction between amyloid β isoforms and its effect on aggregation pathways

Journal of Biomolecular Structure and Dynamics, Год журнала: 2025, Номер unknown, С. 1 - 11

Опубликована: Март 7, 2025

The self-aggregation of amyloid β (Aβ) proteins has played a crucial role in the pathogenesis Alzheimer's diseases. Despite previous studies on aggregation process Aβ proteins, little is known about how cross-interaction between isoforms affects pathways and resulting structures aggregates. Here, we study Aβ40 Aβ42 during their by measuring kinetics aggregates under varied concentrations isoform mixture. We found that mixture monomers results concentration-dependent leading to different aggregate such way induce structural types as sized oligomers or fibrils with morphologies flexibilities. Moreover, investigate effect (or Aβ42) oligomer fibril seeds pathway Aβ40). show fibril) seed not only but also Our sheds light at primary nucleation level its pathways.

Язык: Английский

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Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus

Open Medicine, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 1, 2025

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and β-cell dysfunction. A hallmark of T2DM pathology the accumulation toxic amyloid polypeptides in around pancreatic islet cells, leading to progressive loss populations. Human polypeptide (hIAPP), also known as amylin, 37-amino acid peptide hormone primarily produced β-cells. hIAPP aggregation formation are strongly correlated with death disease severity patients. This article aims review current research progress on correlation between T2DM, focusing molecular mechanisms potential therapeutic strategies. We conducted comprehensive literature covering recent studies structure, physiological function, pathological hIAPP. Key areas include biosynthesis, monomer fiber structures. Additionally, we examined hIAPP-induced death, including oxidative stress (OS), endoplasmic reticulum (ERS), impaired cell membrane mitochondrial functions, inflammatory factors. Our highlights critical role pathogenesis T2DM. Specifically, found that biosynthesis structure contribute its while forms fibers, contributing OS, ERS, factors play significant roles death. There strong approaches using small molecule inhibitors prevent fibrosis discussed. Understanding provides insights into targets preventive Future should focus developing more effective treatments targeting downstream effects.

Язык: Английский

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