scholarly journals Amyloid-Mediated Mechanisms of Membrane Disruption

Biophysica ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 137-156
Author(s):  
Michele F. M. Sciacca ◽  
Carmelo La Rosa ◽  
Danilo Milardi
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Conformational Transition ◽  
Prion Diseases ◽  
Membrane Damage ◽  
Amyloid Β ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Amyloid Aggregates ◽  
Abnormal Accumulation

Protein aggregation and amyloid formation are pathogenic events underlying the development of an increasingly large number of human diseases named “proteinopathies”. Abnormal accumulation in affected tissues of amyloid β (Aβ) peptide, islet amyloid polypeptide (IAPP), and the prion protein, to mention a few, are involved in the occurrence of Alzheimer’s (AD), type 2 diabetes mellitus (T2DM) and prion diseases, respectively. Many reports suggest that the toxic properties of amyloid aggregates are correlated with their ability to damage cell membranes. However, the molecular mechanisms causing toxic amyloid/membrane interactions are still far to be completely elucidated. This review aims at describing the mutual relationships linking abnormal protein conformational transition and self-assembly into amyloid aggregates with membrane damage. A cross-correlated analysis of all these closely intertwined factors is thought to provide valuable insights for a comprehensive molecular description of amyloid diseases and, in turn, the design of effective therapies.

scholarly journals Implications of Metal Binding and Asparagine Deamidation for Amyloid Formation

2018 ◽  
Vol 19 (8) ◽  
pp. 2449 ◽  
Author(s):  
Yutaka Sadakane ◽  
Masahiro Kawahara
Keyword(s):  
Conformational Changes ◽  
Posttranslational Modifications ◽  
Self Assembly ◽  
Metal Binding ◽  
Prion Diseases ◽  
Amyloid Formation ◽  
Amyloidogenic Proteins ◽  
Two Factors ◽  
Asparagine Deamidation ◽  
Β Amyloid

Increasing evidence suggests that amyloid formation, i.e., self-assembly of proteins and the resulting conformational changes, is linked with the pathogenesis of various neurodegenerative disorders such as Alzheimer’s disease, prion diseases, and Lewy body diseases. Among the factors that accelerate or inhibit oligomerization, we focus here on two non-genetic and common characteristics of many amyloidogenic proteins: metal binding and asparagine deamidation. Both reflect the aging process and occur in most amyloidogenic proteins. All of the amyloidogenic proteins, such as Alzheimer’s β-amyloid protein, prion protein, and α-synuclein, are metal-binding proteins and are involved in the regulation of metal homeostasis. It is widely accepted that these proteins are susceptible to non-enzymatic posttranslational modifications, and many asparagine residues of these proteins are deamidated. Moreover, these two factors can combine because asparagine residues can bind metals. We review the current understanding of these two common properties and their implications in the pathogenesis of these neurodegenerative diseases.

The Lipid-Chaperon Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins

2020 ◽  
Author(s):  
Michele F. M. Sciacca ◽  
Fabio Lolicato ◽  
Carmelo Tempra ◽  
Federica Scollo ◽  
Bikash R. Sahoo ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Membrane Damage ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Formation ◽  
Intrinsically Disordered ◽  
Molecular Events ◽  
Membrane Poration ◽  
Synuclein Proteins

<p>Increasing number of human diseases have been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer’s, and Parkinson’s, respectively. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the molecular events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Experimental results from a variety of biophysical methods and molecular dynamics results reveal this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and non-amyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a “lipid-chaperone” hypothesis as a unifying framework for protein-membrane poration.<b></b></p>

scholarly journals Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Diana C Rodriguez Camargo ◽  
Kyle J Korshavn ◽  
Alexander Jussupow ◽  
Kolio Raltchev ◽  
David Goricanec ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Death ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Md Simulations ◽  
Human Islet ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Induce Cell Death

Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique β-strand structure distinct from the conventional amyloid β-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.

scholarly journals Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 134 ◽  
Author(s):  
Anna L. Gharibyan ◽  
Tohidul Islam ◽  
Nina Pettersson ◽  
Solmaz A. Golchin ◽  
Johanna Lundgren ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Formation ◽  
Loss Of Function ◽  
Islet Amyloid ◽  
Amyloid Deposits ◽  
Primary Focus ◽  
The Impact

Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

scholarly journals Aß40 displays amyloidogenic properties in the non-transgenic mouse brain but does not exacerbate Aß42 toxicity in Drosophila.

2020 ◽  
Author(s):  
Lorena de Mena ◽  
Michael A Smith ◽  
Jason Martin ◽  
Katie L Dunton ◽  
Carolina Ceballos-Diaz ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Self Assembly ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Model Systems ◽  
Amyloid Angiopathy ◽  
Amyloid Deposits ◽  
Amyloid Aggregates ◽  
Amyloid Cascade

Abstract Background Self-assembly of the amyloid-β (Aβ) peptide into aggregates, from small oligomers to amyloid fibrils, is fundamentally linked with Alzheimer’s disease (AD). However it is clear that not all forms of Aβ are equally harmful, and that linking a specific aggregate to toxicity also depends on the assays and model systems used [1, 2]. Though a central postulate of the amyloid cascade hypothesis, there remain many gaps in our understanding regarding the links between Aβ deposition and neurodegeneration. Methods In this study, we examined familial mutations of Aβ that increase aggregation and oligomerization, E22G and DE22, and induce cerebral amyloid angiopathy, E22Q and D23N. We also investigated synthetic mutations that stabilize dimerization, S26C, and a phospho-mimetic, S8E, and non-phospho-mimetic, S8A. To that end, we utilized BRI2-Aβ fusion technology and rAAV2/1 based somatic brain transgenesis in mice to selectively express individual mutant Aβ species in vivo. In parallel we generated PhiC31-based transgenic Drosophila melanogaster expressing wild type (WT) and Aβ40 and Aβ42 mutants, fused to the Argos signal peptide to assess the extent of Aβ42-induced toxicity as well as to interrogate the combined effect of different Aβ40 and Aβ42 species.Results When expressed in the mouse brain for 6 months, Aβ42 E22G, Aβ42 E22Q/D23N, and Aβ42WT formed amyloid aggregates consisting of some diffuse material as well as cored plaques, whereas other mutants formed predominantly diffuse amyloid deposits. Moreover, while Aβ40WT showed no distinctive phenotype, Aβ40 E22G and E22Q/D23N formed unique aggregates that accumulated in mouse brains. This is the first evidence that mutant Aβ40 overexpression leads to deposition under certain conditions. Interestingly, we found that mutant Aβ42 E22G, E22Q, and S26C, but not Aβ40, were toxic to the eye of Drosophila. In contrast, flies expressing a copy of Aβ40 (WT or mutants) in addition to Aβ42WT, showed improved phenotypes, suggesting possible protective qualities for Aβ40. Conclusions These studies suggest that while some Aβ40 mutants form unique amyloid aggregates in mouse brains, they do not exacerbate Aβ42 toxicity in Drosophila, which highlights the significance of using different systems for a better understanding of AD pathogenicity and more accurate screening for new potential therapies.

scholarly journals The Amyloid Forming Peptides Islet Amyloid Polypeptide and Amyloid β Interact at the Molecular Level

2021 ◽  
Vol 22 (20) ◽  
pp. 11153
Author(s):  
Ye Wang ◽  
Gunilla T. Westermark
Keyword(s):  
Drosophila Melanogaster ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Epidemiological Studies ◽  
Bimolecular Fluorescence Complementation ◽  
Amyloid Formation ◽  
Islet Amyloid

Epidemiological studies support a connection between the two common disorders, type-2 diabetes and Alzheimer’s disease. Both conditions have local amyloid formation in their pathogenesis, and cross-seeding between islet amyloid polypeptide (IAPP) and amyloid β (Aβ) could constitute the link. The bimolecular fluorescence complementation (BiFC) assay was used to investigate the occurrence of heterologous interactions between IAPP and Aβ and to compare the potential toxic effects of IAPP/Aβ, IAPP/IAPP, and Aβ/Aβ expression in living cells. Microscopy was used to confirm the fluorescence and determine the lysosomal, mitochondrial areas and mitochondrial membrane potential , and a FACS analysis was used to determine ROS production and the role for autophagy. Drosophila melanogaster expressing IAPP and Aβ was used to study their co-deposition and effects on longevity. We showed that the co-expression of IAPP and Aβ resulted in fluorophore reconstitution to the same extent as determined for homologous IAPP/IAPP or Aβ/Aβ expression. The BiFC(+)/BiFC(-) ratio of lysosomal area calculations increased in transfected cells independent of the vector combinations, while only Aβ/Aβ expression increased mitochondrial membrane potential. Expression combinations containing Aβ were necessary for the formation of a congophilic amyloid. In Drosophila melanogaster expressing IAPP/Aβ, co-deposition of the amyloid-forming peptides caused reduced longevity. The BiFC results confirmed a heterologous interaction between IAPP and Aβ, while co-deposits in the brain of Drosophila suggest mixed amyloid aggregates.

Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner

2013 ◽  
Vol 450 (1) ◽  
pp. 189-197 ◽  
Author(s):  
Kristoffer Brännström ◽  
Anders Öhman ◽  
Malin Lindhagen-Persson ◽  
Anders Olofsson
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Mechanistic Explanation ◽  
Elongation Rate ◽  
Polymerization Rate ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

Identifying factors that affect the self-assembly of Aβ (amyloid-β peptide) is of utmost importance in the quest to understand the molecular mechanisms causing AD (Alzheimer's disease). Ca2+ has previously been shown to accelerate both Aβ fibril nucleation and maturation, and dysregulated Ca2+ homoeostasis frequently correlates with development of AD. The mechanisms regarding Ca2+ binding, as well as its effect on fibril kinetics, are not fully understood. Using a polymerization assay we show that Ca2+ in a dynamic and reversible manner enhances both the elongation rate and fibrillar stability, where specifically the ‘dock and lock’ phase mechanism is enhanced. Through NMR analysis we found that Ca2+ affects the fibrillar architecture. In addition, and unexpectedly, we found that Ca2+ does not bind the free Aβ monomer. This implies that Ca2+ binding requires an architecture adopted by assembled peptides, and consequently is mediated through intermolecular interactions between adjacent peptides. This gives a mechanistic explanation to the enhancing effect on fibril maturation and indicates structural similarities between prefibrillar structures and mature amyloid. Taken together we show how Ca2+ levels affect the delicate equilibrium between the monomeric and assembled Aβ and how fluctuations in vivo may contribute to development and progression of the disease.

scholarly journals Amyloidogenicity and cytotoxicity of des-Lys-1 human amylin provides insight into amylin self-assembly and highlights the difficulties of defining amyloidogenicity

2019 ◽  
Vol 32 (2) ◽  
pp. 87-93 ◽  
Author(s):  
Kyung-Hoon Lee ◽  
Alexander Zhyvoloup ◽  
Daniel Raleigh
Keyword(s):  
Self Assembly ◽  
Amyloid Formation ◽  
Wild Type ◽  
Islet Amyloid ◽  
High Charge Density ◽  
Human Amylin ◽  
Phosphate Buffered Saline

Abstract The polypeptide amylin is responsible for islet amyloid in type 2 diabetes, a process which contributes to β-cell death in the disease. The role of the N-terminal region of amylin in amyloid formation is relatively unexplored, although removal of the disulfide bridged loop between Cys-2 and Cys-7 accelerates amyloid formation. We examine the des Lys-1 variant of human amylin (h-amylin), a variant which is likely produced in vivo. Lys-1 is a region of high charge density in the h-amylin amyloid fiber. The des Lys-1 polypeptide forms amyloid on the same time scale as wild-type amylin in phosphate buffered saline, but does so more rapidly in Tris. The des Lys-1 variant is somewhat less toxic to cultured INS cells than wild type. The implications for the in vitro mechanism of amyloid formation and for comparative analysis of amyloidogenicity are discussed.

scholarly journals β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 796
Author(s):  
Noyonika Mukherjee ◽  
Li Lin ◽  
Christopher J. Contreras ◽  
Andrew T. Templin
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Pathological Process ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Regulated Necrosis ◽  
Islet Inflammation ◽  
Stress Oxidative

β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.

scholarly journals Cold Atmospheric Plasma Modification of Amyloid β

2021 ◽  
Vol 22 (6) ◽  
pp. 3116
Author(s):  
Maho Yagi-Utsumi ◽  
Tomohiro Tanaka ◽  
Yoko Otsubo ◽  
Akira Yamashita ◽  
Shinji Yoshimura ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Structures ◽  
Amyloid Β ◽  
Atmospheric Plasma ◽  
Plasma Modification ◽  
Resonance Spectroscopy ◽  
Amyloid Formation ◽  
Cold Atmospheric Plasma ◽  
Methionine Residue ◽  
Aβ Amyloid

Cold atmospheric plasma (CAP) has attracted much attention in the fields of biotechnology and medicine owing to its potential utility in clinical applications. Recently accumulating evidence has demonstrated that CAP influences protein structures. However, there remain open questions regarding the molecular mechanisms behind the CAP-induced structural perturbations of biomacromolecules. Here, we investigated the potential effects of CAP irradiation of amyloid β (Aβ), an amyloidogenic protein associated with Alzheimer’s disease. Using nuclear magnetic resonance spectroscopy, we observed gradual spectral changes in Aβ after a 10 s CAP pretreatment, which also suppressed its fibril formation, as revealed by thioflavin T assay. As per mass spectrometric analyses, these effects were attributed to selective oxidation of the methionine residue (Met) at position 35. Interestingly, this modification occurred when Aβ was dissolved into a pre-irradiated buffer, indicating that some reactive species oxidize the Met residue. Our results strongly suggest that the H2O2 generated in the solution by CAP irradiation is responsible for Met oxidation, which inhibits Aβ amyloid formation. The findings of the present study provide fundamental insights into plasma biology, giving clues for developing novel applications of CAP.

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