Huntingtin exon 1 fibrils feature an interdigitated β-hairpin-based polyglutamine core

Polyglutamine expansion within the exon1 of huntingtin leads to protein misfolding, aggregation, and cytotoxicity in Huntington’s Disease. This incurable neurodegenerative disease is the most prevalent member of a family of CAG repeat expansion disorders. Although mature exon1 fibrils are viable candidates for the toxic species, their molecular structure and how they form have remained poorly understood. Using advanced magic angle spinning solid state NMR, we directly probe the structure of the rigid core that is at the heart of huntingtin exon1 fibrils and other polyglutamine aggregates, via measurements of long-range intra- and inter-molecular contacts, backbone and side chain torsion angles, relaxation measurements, and calculations of chemical shifts. These reveal the presence of β-hairpin-containing β-sheets that are connected through interdigitating extended side chains. Despite dramatic differences in aggregation behavior, huntingtin exon1 fibrils and other polyglutamine-based aggregates contain identical β-strand-based cores. Prior structural models, derived from X-ray fiber diffraction and computational analyses, are shown to be inconsistent with the solid-state NMR results. Internally, the polyglutamine amyloid fibrils are co-assembled from differently structured monomers, which we describe as a type of ‘intrinsic’ polymorphism. A stochastic polyglutamine-specific aggregation mechanism is introduced to explain this phenomenon. Weshow that the aggregation of mutant huntingtin exon1 proceeds via an intramolecular collapse of the expanded polyglutamine domain, and discuss the implications of this observation for our understanding of its misfolding and aggregation mechanisms

Aascharjya Charjyachaya = ଆଶ୍ଚର୍ଯ୍ୟ ଚର୍ଜାଚୟ

A collection of Boudha Gan and Doha - the earliest Oriya compositions. The book presents 46 compositions by different saints

Capsaicin-Coated Silver Nanoparticles Inhibit Amyloid Fibril Formation of Serum Albumin

We have synthesized capsaicin-coated silver nanoparticles (AgNPs^Cap) and have tested their anti-amyloid activity, considering serum albumin (BSA) as a model protein. We found that amyloid formation of BSA was strongly suppressed in the presence of AgNPs^Cap. However, isolated capsaicin and uncapped control nanoparticles did not show such an inhibition effect. Bioinformatics analysis reveals CH−π and H-bonding interactions between capsaicin and BSA in the formation of the protein–ligand complex. These results suggest the significance of surface functionalization of nanoparticles with capsaicin, which probably allows capsaicin to effectively interact with the key residues of the amyloidogenic core of BSA

Evidence of Rapid Coaggregation of Globular Proteins during Amyloid Formation

The question of how an aggregating protein can influence aggregation of other proteins located in its vicinity is particularly significant because many proteins coexist in cells. We demonstrate <i>in vitro</i> coaggregation and cross-seeding of lysozyme, bovine serum albumin, insulin, and cytochrome <i>c</i> during their amyloid formation. The coaggregation process seems to be more dependent on the temperature-induced intermediate species of these proteins and less dependent on their sequence identities. Because amyloid-linked inclusions and plaques are recognized as multicomponent entities originating from aggregation of the associated protein, these findings may add new insights into the mechanistic understanding of amyloid-related pathologies

Uniform, Polycrystalline, and Thermostable Piperine-Coated Gold Nanoparticles to Target Insulin Fibril Assembly

Because the process of insulin fibril assembly is linked to a multitude of medical problems, finding effective and biocompatible inhibitors against such an aggregation process could be beneficial. Targeting the aggregation-prone residues of insulin may perhaps work as an effective strategy to prevent the onset of insulin fibril assembly. In this work, we have synthesized uniform sized, thermostable gold nanoparticles (AuNPs^piperine) surface-functionalized with piperine to target amyloid-prone residues of insulin. We found that the process of both spontaneous and seed-induced amyloid formation of insulin was strongly inhibited in the presence of AuNPs^piperine. Surface functionalization of piperine was found to be critical to its inhibition effect because no such effect was observed for free piperine as well as for uncoated control gold nanoparticles. Fluorescence quenching data revealed binding of AuNPs^piperine with insulin’s native structure which was further validated by docking studies that predicted viable H-bond and CH-π interactions between piperine and key aggregation-prone residues of insulin’s B-chain. Our hemolysis assay studies further confirmed that these piperine coated nanoparticles were hemocompatible. Data obtained from both experimental and computational studies suggest that the retention of native structure of insulin and the ability of the piperine molecule to interact with the aggregation-prone residues of insulin are the key factors for the inhibition mechanism. The findings of this work may help in the development of nanoparticle-based formulations to prevent medical problems linked to insulin aggregation

Strategically Designed Antifibrotic Gold Nanoparticles to Prevent Collagen Fibril Formation

Because uncontrolled accumulation of collagen fibrils has been implicated in a series of pathologies, inhibition of collagen fibril formation has become one of the necessary strategies to target such collagen-linked complications. The presence of hydroxyproline (<i>Hyp</i>) at the Y position in (Gly-X-Y)_<i>n</i> sequence pattern of collagen is known to facilitate crucial hydrophobic and hydration-linked interactions that promote collagen fibril formation. Here, to target such <i>Hyp</i>-mediated interactions, we have synthesized uniform, thermostable, and hemocompatible <i>Hyp</i> coated gold nanoparticles (AuNPs^HYP) and have examined their inhibition effect on the fibril formation of type I collagen. We found that collagen fibril formation is strongly suppressed in the presence of AuNPs^HYP and no such suppression effect was observed in the presence of free <i>Hyp</i> and control Gly-coated nanoparticles at similar concentrations. Both isothermal titration calorimetric studies and bioinformatics analysis reveal possible interaction between <i>Hyp</i> and (Gly-Pro-Hyp) stretches of collagen triple-helical model peptides. Further, gold nanoparticles coated with proline (AuNPs^PRO) and tryptophan (AuNPs^TRP) also suppressed collagen fibril formation, suggesting their ability to interfere with aromatic-proline as well as hydrophobic interactions between collagen molecules. The <i>Hyp</i> molecules, when surface functionalized, are predicted to interfere with the <i>Hyp</i>-mediated forces that drive collagen self-assembly, and such inhibition effect may help in targeting collagen linked pathologies