scholarly journals Sequestration within biomolecular condensates inhibits Aβ-42 amyloid formation

2021 ◽  
Vol 12 (12) ◽  
pp. 4373-4382
Author(s):  
Andreas M. Küffner ◽  
Miriam Linsenmeier ◽  
Fulvio Grigolato ◽  
Marc Prodan ◽  
Remo Zuccarini ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Formation ◽  
Local Increase ◽  
Heterotypic Interactions

Biomolecular condensates sequester an aggregation-prone peptide and prevent its aggregation, showing that heterotypic interactions within the condensates can prevent the formation of amyloid fibrils, despite the local increase in concentration.

scholarly journals Apomorphine Targets the Pleiotropic Bacterial Regulator Hfq

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 257
Author(s):  
Florian Turbant ◽  
David Partouche ◽  
Omar El Hamoui ◽  
Sylvain Trépout ◽  
Théa Legoubey ◽  
...  
Keyword(s):  
Small Rnas ◽  
Antibacterial Agents ◽  
Amyloid Fibrils ◽  
Noncoding Rnas ◽  
Amyloid Formation ◽  
Gram Negative Bacteria ◽  
Translation Efficiency ◽  
Gram Negative ◽  
Bacterial Adaptation ◽  
E Coli

Hfq is a bacterial regulator with key roles in gene expression. The protein notably regulates translation efficiency and RNA decay in Gram-negative bacteria, thanks to its binding to small regulatory noncoding RNAs. This property is of primary importance for bacterial adaptation and survival in hosts. Small RNAs and Hfq are, for instance, involved in the response to antibiotics. Previous work has shown that the E. coli Hfq C-terminal region (Hfq-CTR) self-assembles into an amyloid structure. It was also demonstrated that the green tea compound EpiGallo Catechin Gallate (EGCG) binds to Hfq-CTR amyloid fibrils and remodels them into nonamyloid structures. Thus, compounds that target the amyloid region of Hfq may be used as antibacterial agents. Here, we show that another compound that inhibits amyloid formation, apomorphine, may also serve as a new antibacterial. Our results provide an alternative in order to repurpose apomorphine, commonly used in the treatment of Parkinson’s disease, as an antibiotic to block bacterial adaptation to treat infections.

scholarly journals Deletion of Serf2 shifts amyloid conformation in an Aβ amyloid mouse model

2021 ◽  
Author(s):  
E. Stroo ◽  
L. Janssen ◽  
O. Sin ◽  
W. Hogewerf ◽  
M. Koster ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amyloid Fibrils ◽  
Mammalian Brain ◽  
Amyloid Formation ◽  
List Type ◽  
Lung Maturation ◽  
Disease Manifestation ◽  
Aβ Amyloid ◽  
Perinatal Lethality

AbstractNeurodegenerative diseases like Alzheimer, Parkinson and Huntington disease are characterized by aggregation-prone proteins that form amyloid fibrils through a nucleation process. Despite the shared β-sheet structure, recent research has shown that structurally different polymorphs exist within fibrils of the same protein. These polymorphs are associated with varying levels of toxicity and different disease phenotypes. MOAG-4 and its human orthologs SERF1 and SERF2 have previously been shown to modify the nucleation and drive amyloid formation and protein toxicity in vitro and in C. elegans. To further explore these findings, we generated a Serf2 knockout (KO) mouse model and crossed it with the APPPS1 mouse model for Aβ amyloid pathology. Full-body KO of Serf2 resulted in a developmental delay and perinatal lethality due to insufficient lung maturation. Therefore, we proceeded with a brain-specific Serf2 KO, which was found to be viable. We examined the Aβ pathology at 1 and 3 months of age, which is before and after the start of amyloid deposition. We show that SERF2 deficiency does not affect the production and overall Aβ levels. Serf2 KO-APPPS1 mice displayed an increased intracellular Aβ accumulation at 1 month and a higher number of Aβ deposits compared to APPPS1 mice with similar Aβ levels. Moreover, conformation-specific dyes and electron microscopy revealed a difference in the structure and amyloid content of these Aβ deposits. Together, our results reveal that SERF2 causes a structural shift in Aβ aggregation in a mammalian brain. These findings indicate that a single endogenous factor may contribute to amyloid polymorphisms, allowing for new insights into this phenomenon’s contribution to disease manifestation.HighlightsLoss of SERF2 slows embryonic development and causes perinatal lethalitySERF2 affects proliferation in a cell-autonomous fashionBrain-specific Serf2 knockout does not affect viability or Aβ productionBrain deletion of Serf2 shifts the amyloid conformation of Aβ

Abstract 539: Soluble Oxidized Apolipoprotein A-I, a Precursor of Amyloid Fibrils, Activates Secretion of Inflammatory Cytokines in Macrophages

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Andrzej Witkowski ◽  
Gary K Chan ◽  
Nancy J Li ◽  
Rui Lu ◽  
Shinji Yokoyama ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Amyloid Fibrils ◽  
Mouse Bone Marrow ◽  
Amyloid Formation ◽  
Cellular Cholesterol ◽  
Atherosclerosis Progression ◽  
Apolipoprotein A ◽  
Inflammatory Protein ◽  
Release Capacity

Atherosclerosis is often described as an inflammatory disease of the arteries. One mechanism whereby apolipoprotein A-I (apoA-I) exerts its anti-atherosclerotic effect is by mitigating the inflammatory response of cells involved in atherosclerosis progression. However, oxidation transforms apoA-I from an anti-inflammatory to a pro-inflammatory protein. We previously reported that oxidation can also promote apoA-I aggregation and formation of amyloid fibrils. In this study, we investigated the mechanistic interplay between oxidation, amyloid formation and the inflammatory response of macrophages to apoA-I. We hypothesized that amyloid fibrils constituted of oxidized apoA-I activate production of inflammatory cytokines in macrophages. To test this hypothesis, amyloidogenic apoA-I was generated by oxidation with an excess of H 2 O 2 (H 2 O 2 -ApoA-I). Intracellular and secreted levels of IL-1β were determined upon incubation of mouse bone marrow derived macrophages (BMDM) with intact-apoA-I, soluble H 2 O 2 -ApoA-I and pre-formed H 2 O 2 -ApoA-I amyloid fibrils. Cellular cholesterol release from RAW264.7 cells was also measured. Soluble H 2 O 2 -ApoA-I (amyloid precursor) retained the cellular cholesterol release capacity of intact-ApoA-I. In BMDM incubated with soluble H 2 O 2 -ApoA-I however, levels of IL-1β synthesis and secretion were at least 2-fold higher than those induced by intact-ApoA-I. In contrast, incubation with H 2 O 2 -ApoA-I amyloid fibrils did not increase the levels of IL-1β synthesis and secretion, compared to intact-ApoA-I. Thus, soluble and functional oxidized apoA-I activates inflammatory cytokine synthesis and secretion in macrophages. Notably, this pro-inflammatory potential was completely neutralized when oxidized apoA-I was aggregated in amyloids. Therefore in atherosclerotic lesions, amyloid formation could reduce, rather than exacerbate, the inflammatory burden produced by pro-inflammatory soluble oxidized apoA-I species.

scholarly journals Synaptic vesicle mimics affect the aggregation of wild-type and A53T α-synuclein variants differently albeit similar membrane affinity

2019 ◽  
Vol 32 (2) ◽  
pp. 59-66
Author(s):  
Sandra Rocha ◽  
Ranjeet Kumar ◽  
Istvan Horvath ◽  
Pernilla Wittung-Stafshede
Keyword(s):  
Synaptic Vesicles ◽  
Amyloid Fibrils ◽  
Membrane Surface ◽  
Amyloid Formation ◽  
Wild Type ◽  
Membrane Affinity ◽  
Axis Parallel ◽  
Biophysical Techniques ◽  
Small Unilamellar Vesicles ◽  
The Brain

Abstract α-Synuclein misfolding results in the accumulation of amyloid fibrils in Parkinson’s disease. Missense protein mutations (e.g. A53T) have been linked to early onset disease. Although α-synuclein interacts with synaptic vesicles in the brain, it is not clear what role they play in the protein aggregation process. Here, we compare the effect of small unilamellar vesicles (lipid composition similar to synaptic vesicles) on wild-type (WT) and A53T α-synuclein aggregation. Using biophysical techniques, we reveal that binding affinity to the vesicles is similar for the two proteins, and both interact with the helix long axis parallel to the membrane surface. Still, the vesicles affect the aggregation of the variants differently: effects on secondary processes such as fragmentation dominate for WT, whereas for A53T, fibril elongation is mostly affected. We speculate that vesicle interactions with aggregate intermediate species, in addition to monomer binding, vary between WT and A53T, resulting in different consequences for amyloid formation.

Light Microscopic, Immunohistochemical, and Electron Microscopic Features of Amyloid Arthropathy in Chickens

1997 ◽  
Vol 34 (4) ◽  
pp. 271-278 ◽  
Author(s):  
N. H. M. T. Peperkamp ◽  
W. J. M. Landman ◽  
P. C. J. Tooten ◽  
A. Ultee ◽  
W. F. Voorhout ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Enterococcus Faecalis ◽  
Amyloid Fibrils ◽  
Superficial Layer ◽  
Immunogold Electron Microscopy ◽  
Amyloid Formation ◽  
Electron Microscopic ◽  
Amyloid A ◽  
Amyloid Deposits ◽  
Amyloid Arthropathy

Amyloid arthropathy has been recently recognized as a spontaneous syndrome in chickens. Predominantly, femorotibial and tarsometatarsal joints were affected, showing (peri) articular orange amyloid deposits. Immunohistochemical evaluation revealed the amyloid to be of the reactive type. Induction of amyloid arthropathy in chickens was carried out using a single intravenous injection of Enterococcus faecalis cultures. In the naturally occurring and the induced cases, amyloid deposits were found in the hypertrophic synovial villi and in the articular cartilage, particularly in the superficial layer and in the nutritional blood vessel walls. Highly sulfated glycosaminoglycans (GAGs) were found in the amyloid deposits. Ultrastructurally, bundles of amyloid fibrils were seen in invaginations of synoviocytes and chondrocytes. Immunogold electron microscopy failed to reveal signs of intracellular amyloid formation. The predilection site for amyloid deposition in the major leg joints of the chickens with reactive amyloid could be explained by the arthritic condition caused by Enterococcus faecalis bacteriaemia. The polyarthritis triggers hepatic acute phase protein synthesis and increases the vascular serum amyloid A (SAA) supply to the joint. Inflammatory and degenerative changes in the articular cartilage and adjoining tissues result in an increase of highly sulphated GAGs, which are considered to enhance deposition of SAA as amyloid.

scholarly journals Modulating functional amyloid formation via alternative splicing of the premelanosomal protein PMEL17

2020 ◽  
Vol 295 (21) ◽  
pp. 7544-7553 ◽  
Author(s):  
Dexter N. Dean ◽  
Jennifer C. Lee
Keyword(s):  
Alternative Splicing ◽  
Amyloid Fibrils ◽  
Limited Proteolysis ◽  
Amyloid Formation ◽  
Functional Amyloid ◽  
Melanin Biosynthesis ◽  
Functional Amyloids ◽  
Fibril Morphology ◽  
Amyloid Assembly ◽  
Β Sheet

The premelanosomal protein (PMEL17) forms functional amyloid fibrils involved in melanin biosynthesis. Multiple PMEL17 isoforms are produced, two of which arise from excision of a cryptic intron within the amyloid-forming repeat (RPT) domain, leading to long (lRPT) and short (sRPT) isoforms with 10 and 7 imperfect repeats, respectively. Both lRPT and sRPT isoforms undergo similar pH-dependent mechanisms of amyloid formation and fibril dissolution. Here, using human PMEL17, we tested the hypothesis that the minor, but more aggregation-prone, sRPT facilitates amyloid formation of lRPT. We observed that cross-seeding by sRPT fibrils accelerates the rate of lRPT aggregation, resulting in propagation of an sRPT-like twisted fibril morphology, unlike the rodlike structure that lRPT normally adopts. This templating was specific, as the reversed reaction inhibited sRPT fibril formation. Despite displaying ultrastructural differences, self- and cross-seeded lRPT fibrils had a similar β-sheet structured core, revealed by Raman spectroscopy, limited-proteolysis, and fibril disaggregation experiments, suggesting the fibril twist is modulated by N-terminal residues outside the amyloid core. Interestingly, bioinformatics analysis of PMEL17 homologs from other mammals uncovered that long and short RPT isoforms are conserved among members of this phylogenetic group. Collectively, our results indicate that the short isoform of RPT serves as a “nucleator” of PMEL17 functional amyloid formation, mirroring how bacterial functional amyloids assemble during biofilm formation. Whereas bacteria regulate amyloid assembly by using individual genes within the same operon, we propose that the modulation of functional amyloid formation in higher organisms can be accomplished through alternative splicing.

scholarly journals Amylin, Aβ42, and Amyloid in Varicella Zoster Virus Vasculopathy Cerebrospinal Fluid and Infected Vascular Cells

2020 ◽  
Author(s):  
Andrew N Bubak ◽  
Cheryl Beseler ◽  
Christina N Como ◽  
Christina M Coughlan ◽  
Noah R Johnson ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Varicella Zoster Virus ◽  
Amyloid Fibrils ◽  
Central Nervous System Infection ◽  
Amyloid Deposition ◽  
Amyloid Formation ◽  
Varicella Zoster ◽  
Arterial Inflammation ◽  
Amyloidogenic Peptides ◽  
Interfering Rna

Abstract Background Varicella zoster virus (VZV) vasculopathy is characterized by persistent arterial inflammation leading to stroke. Studies show that VZV induces amyloid formation that may aggravate vasculitis. Thus, we determined if VZV central nervous system infection produces amyloid. Methods Aβ peptides, amylin, and amyloid were measured in cerebrospinal fluid (CSF) from 16 VZV vasculopathy subjects and 36 stroke controls. To determine if infection induced amyloid deposition, mock- and VZV-infected quiescent primary human perineurial cells (qHPNCs), present in vasculature, were analyzed for intracellular amyloidogenic transcripts/proteins and amyloid. Supernatants were assayed for amyloidogenic peptides and ability to induce amyloid formation. To determine amylin’s function during infection, amylin was knocked down with small interfering RNA and viral complementary DNA (cDNA) was quantitated. Results Compared to controls, VZV vasculopathy CSF had increased amyloid that positively correlated with amylin and anti-VZV antibody levels; Aβ40 was reduced and Aβ42 unchanged. Intracellular amylin, Aβ42, and amyloid were seen only in VZV-infected qHPNCs. VZV-infected supernatant formed amyloid fibrils following addition of amyloidogenic peptides. Amylin knockdown decreased viral cDNA. Conclusions VZV infection increased levels of amyloidogenic peptides and amyloid in CSF and qHPNCs, indicating that VZV-induced amyloid deposition may contribute to persistent arterial inflammation in VZV vasculopathy. In addition, we identified a novel proviral function of amylin.

scholarly journals Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers

2019 ◽  
Vol 116 (34) ◽  
pp. 16835-16840 ◽  
Author(s):  
Niraja Kedia ◽  
Khalid Arhzaouy ◽  
Sara K. Pittman ◽  
Yuanzi Sun ◽  
Mark Batchelor ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Therapeutic Potential ◽  
Epigallocatechin Gallate ◽  
Amyloid Formation ◽  
Myofibrillar Myopathy ◽  
Protein Aggregate ◽  
Disease Mutations ◽  
Amyloid Aggregates ◽  
Associated Proteins

Desmin-associated myofibrillar myopathy (MFM) has pathologic similarities to neurodegeneration-associated protein aggregate diseases. Desmin is an abundant muscle-specific intermediate filament, and disease mutations lead to its aggregation in cells, animals, and patients. We reasoned that similar to neurodegeneration-associated proteins, desmin itself may form amyloid. Desmin peptides corresponding to putative amyloidogenic regions formed seeding-competent amyloid fibrils. Amyloid formation was increased when disease-associated mutations were made within the peptide, and this conversion was inhibited by the anti-amyloid compound epigallocatechin-gallate. Moreover, a purified desmin fragment (aa 117 to 348) containing both amyloidogenic regions formed amyloid fibrils under physiologic conditions. Desmin fragment-derived amyloid coaggregated with full-length desmin and was able to template its conversion into fibrils in vitro. Desmin amyloids were cytotoxic to myotubes and disrupted their myofibril organization compared with desmin monomer or other nondesmin amyloids. Finally, desmin fragment amyloid persisted when introduced into mouse skeletal muscle. These data suggest that desmin forms seeding-competent amyloid that is toxic to myofibers. Moreover, small molecules known to interfere with amyloid formation and propagation may have therapeutic potential in MFM.

scholarly journals Structure and Aggregation Mechanisms in Amyloids

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1195 ◽  
Author(s):  
Zaida L. Almeida ◽  
Rui M. M. Brito
Keyword(s):  
Molecular Species ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Current Knowledge ◽  
Point Of View ◽  
Resonance Spectroscopy ◽  
Amyloid Formation ◽  
Amyloid Fibril Formation ◽  
Misfolding Diseases ◽  
Amyloid Cascade

The aggregation of a polypeptide chain into amyloid fibrils and their accumulation and deposition into insoluble plaques and intracellular inclusions is the hallmark of several misfolding diseases known as amyloidoses. Alzheimer′s, Parkinson′s and Huntington’s diseases are some of the approximately 50 amyloid diseases described to date. The identification and characterization of the molecular species critical for amyloid formation and disease development have been the focus of intense scrutiny. Methods such as X-ray and electron diffraction, solid-state nuclear magnetic resonance spectroscopy (ssNMR) and cryo-electron microscopy (cryo-EM) have been extensively used and they have contributed to shed a new light onto the structure of amyloid, revealing a multiplicity of polymorphic structures that generally fit the cross-β amyloid motif. The development of rational therapeutic approaches against these debilitating and increasingly frequent misfolding diseases requires a thorough understanding of the molecular mechanisms underlying the amyloid cascade. Here, we review the current knowledge on amyloid fibril formation for several proteins and peptides from a kinetic and thermodynamic point of view, the structure of the molecular species involved in the amyloidogenic process, and the origin of their cytotoxicity.

scholarly journals Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy

2017 ◽  
Vol 11 ◽  
pp. 117954681773032 ◽  
Author(s):  
Marla B Sultan ◽  
Balarama Gundapaneni ◽  
Jennifer Schumacher ◽  
Jeffrey H Schwartz
Keyword(s):  
Disease Progression ◽  
Amyloid Fibrils ◽  
Early Stage ◽  
Heart Association ◽  
Analysis Data ◽  
Amyloid Formation ◽  
Functional Classification ◽  
Wild Type ◽  
Open Label ◽  
Transthyretin Amyloidosis

Background: Transthyretin cardiomyopathy (TTR-CM) is a progressive, fatal disease caused by the accumulation of misfolded transthyretin (TTR) amyloid fibrils in the heart. Tafamidis is a kinetic stabilizer of TTR that inhibits misfolding and amyloid formation. Methods: In this post hoc analysis, data from an observational study (Transthyretin Amyloidosis Cardiac Study; n = 29) were compared with an open-label study of tafamidis in patients with TTR-CM (Fx1B-201; n = 35). To ensure comparable baseline disease severity, patients with New York Heart Association (NYHA) functional classification ≥III were excluded in this time-to-mortality analysis. Results: Patients with either wild-type or Val122Ile genotypes treated with tafamidis have a significantly longer time to death compared with untreated patients ( P = .0004). Similar results were obtained when limiting the analysis to wild-type patients only, without restricting NYHA functional classification ( P = .0262). Conclusions: These results support earlier conclusions suggesting that tafamidis slows disease progression compared with no treatment outside of standard of care and warrant further investigation. Trial Registration: ClinicalTrials.gov, NCT00694161.

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