|
1
|
Shukla M, Narayan M. Proteostasis and Its Role in Disease Development. Cell Biochem Biophys 2024:10.1007/s12013-024-01581-6. [PMID: 39422790 DOI: 10.1007/s12013-024-01581-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2024] [Indexed: 10/19/2024]
Abstract
Proteostasis (protein homeostasis) refers to the general biological process that maintains the proper balance between the synthesis of proteins, their folding, trafficking, and degradation. It ensures proteins are functional, locally distributed, and appropriately folded inside cells. Genetic information enclosed in mRNA is translated into proteins. To ensure newly synthesized proteins take on the exact three-dimensional conformation, molecular chaperones assist in proper folding. Misfolded proteins can be refolded or targeted for elimination to stop aggregation. Cells utilize different degradation pathways, for instance, the ubiquitin-proteasome system, the autophagy-lysosome pathway, and the unfolded protein response, to degrade unwanted or damaged proteins. Quality control systems of the cell monitor the folding of proteins. These checkpoint mechanisms are aimed at degrading or refolding misfolded or damaged proteins. Under stress response pathways, such as heat shock response and unfolded protein response, which are triggered under conditions that perturb proteostasis, the capacity for folding is increased, and degradation pathways are activated to help cells handle stressful conditions. The deregulation of proteostasis is implicated in a variety of illnesses, comprising cancer, metabolic diseases, cardiovascular diseases, and neurological disorders. Therapeutic strategies with a deeper insight into the mechanism of proteostasis are crucial for the treatment of illnesses linked with proteostasis and to support cellular health. Thus, proteostasis is required not only for the maintenance of cellular homeostasis and function but also for proper protein function and prevention of injurious protein aggregation. In this review, we have covered the concept of proteostasis, its mechanism, and how disruptions to it can result in a number of disorders.
Collapse
Affiliation(s)
- Manisha Shukla
- Department of Biotechnology, Pandit S.N. Shukla University, Shahdol, Madhya Pradesh, India
| | - Mahesh Narayan
- Department of Chemistry and Biochemistry, University of Texas, El Paso, TX, USA.
| |
Collapse
|
|
2
|
Xia P, Cao Y, Zhao Q, Li H. Energy gap of conformational transition related with temperature for the NACore of α-synuclein. Phys Chem Chem Phys 2024; 26:23062-23072. [PMID: 39175373 DOI: 10.1039/d4cp02131b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2024]
Abstract
Pathological aggregation of α-synuclein (α-syn) into amyloid fibrils is a major feature of Parkinson's disease (PD). The self-assembly of α-syn is mainly governed by a non-amyloid-β component core (NACore). However, the effects of concentrations and temperatures on their conformational transition remain unclear. To answer this question, we investigated the aggregation kinetics of NACore oligomers in silico by performing several independent all-atom molecular dynamics simulations. The simulation results show that tetramers are more prone to form β-sheets at 300 K than dimers and octamers. We also found that the NACore oligomers had higher β-sheet and β-barrel contents at 310 K. The inter-chain hydrophobic interactions, the backbone hydrogen bonding, the residue-residue interactions between V70-V77 as well as V77-V77 play important roles in the aggregation tendency of NACore octamers at 310 K. Interestingly, the energy gap analysis revealed that the conformational transition of NACore oligomers from intermediate states (β-barrel conformation) to stable structures (β-sheet layers) was dependent on the temperatures. In short, our study provides insight into the kinetic and thermodynamic mechanisms of the conformational transition of NACore at different concentrations and temperatures, contributing to a better understanding of the aggregation process of α-syn in Parkinson's disease.
Collapse
Affiliation(s)
- Pengxuan Xia
- College of Mathematics and Physics, Shanghai University of Electric Power, Shanghai 200090, China
| | - Yuanming Cao
- College of Mathematics and Physics, Shanghai University of Electric Power, Shanghai 200090, China
| | - Qingjie Zhao
- The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Huiyu Li
- College of Mathematics and Physics, Shanghai University of Electric Power, Shanghai 200090, China
| |
Collapse
|
|
3
|
Muñoz-Gutiérrez C, Adasme-Carreño F, Alzate-Morales J, Ireta J. Effect of strand register in the stability and reactivity of crystals from peptides forming amyloid fibrils. Phys Chem Chem Phys 2023; 25:23885-23893. [PMID: 37642522 DOI: 10.1039/d3cp01762a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Amyloids are cytotoxic protein aggregates that deposit in human tissues, leading to several health disorders. Their aggregates can also exhibit catalytic properties, and they have been used as candidates for the development of functional biomaterials. Despite being polymorphic, amyloids often assemble as cross-β fibrils formed by in-register β sheet layers. Recent studies of some amyloidogenic protein segments revealed that they crystallize as antiparallel out-of-register β sheets. Such arrangement has been proposed to be responsible for the cytotoxicity in amyloid diseases, however, there is still no consensus on the molecular mechanism. Interestingly, two amyloidogenic peptide segments, NFGAILS and FGAILSS, arrange into out-of-register and in-register β sheets, respectively, even though they solely differ by one aminoacid residue at both termini. In this work, we used density functional theory (DFT) to address how the strand register contributes into the packing and molecular properties of the NFGAILS and FGAILSS crystals. Our results show that the out-of-register structure is substantially more stable, at 0 K, than the in-register one due to stronger inter-strand contacts. Based on an analysis of the electrostatic potential of the crystal slabs, it is suggested that the out-of-register may potentially interact with negatively charged groups, like those found in cell membranes. Moreover, calculated reactivity descriptors indicate a similar outcome, where only the out-of-register peptide exhibits intrinsic reactive surface sites at the exposed amine and carboxylic groups. It is therefore suggested that the out-of-register arrangement may indeed be crucial for amyloid cytotoxicity. The findings presented here could help to further our understanding of amyloid aggregation, function, and toxicity.
Collapse
Affiliation(s)
- Camila Muñoz-Gutiérrez
- Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Campus Talca, 1 Poniente No. 1141, Box 721, Talca, Chile
| | - Francisco Adasme-Carreño
- Centro de Investigación de Estudios Avanzados del Maule (CIEAM), Vicerrectoría de Investigación y Postgrado, Universidad Católica del Maule, Talca 3480112, Chile
- Laboratorio de Bioinformática y Química Computacional (LBQC), Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3480112, Chile
| | - Jans Alzate-Morales
- Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Campus Talca, 1 Poniente No. 1141, Box 721, Talca, Chile
| | - Joel Ireta
- Departamento de Química, División de Ciencias Básicas e Ingeniería, Universidad Autónoma Metropolitana-Iztapalapa, A.P. 55-534, Ciudad de México 09340, Mexico.
| |
Collapse
|
|
4
|
Li MH, Zhang X, London E, Raleigh DP. Impact of Ca 2+ on membrane catalyzed IAPP amyloid formation and IAPP induced vesicle leakage. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2023; 1865:184161. [PMID: 37121365 PMCID: PMC10735052 DOI: 10.1016/j.bbamem.2023.184161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 04/10/2023] [Accepted: 04/24/2023] [Indexed: 05/02/2023]
Abstract
Human islet amyloid polypeptide (hIAPP, also known as amylin) is a 37 amino acid pancreatic polypeptide hormone that plays a role in regulating glucose levels, but forms pancreatic amyloid in type-2 diabetes. The process of amyloid formation by hIAPP contributes to β-cell death in the disease. Multiple mechanisms of hIAPP induced toxicity of β-cells have been proposed including disruption of cellular membranes. However, the nature of hIAPP membrane interactions and the effect of ions and other molecules on hIAPP membrane interactions are not fully understood. Many studies have used model membranes with a high content of anionic lipids, often POPS, however the concentration of anionic lipids in the β-cell plasma membrane is low. Here we study the concentration dependent effect of Ca2+ (0 to 50 mM) on hIAPP membrane interactions using large unilamellar vesicles (LUVs) with anionic lipid content ranging from 0 to 50 mol%. We find that Ca2+ does not effectively inhibit hIAPP amyloid formation and hIAPP induced membrane leakage from binary LUVs with a low percentage of POPS, but has a greater effect on LUVs with a high percentage of POPS. Mg2+ had very similar effects, and the effects of Ca2+ and Mg2+ can be largely rationalized by the neutralization of POPS charge. The implications for hIAPP-membrane interactions are discussed.
Collapse
Affiliation(s)
- Ming-Hao Li
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, NY 11794, United States
| | - Xiaoxue Zhang
- Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States
| | - Erwin London
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, NY 11794, United States; Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, United States.
| | - Daniel P Raleigh
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, NY 11794, United States; Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United States.
| |
Collapse
|
|
5
|
Ren H, Dommaraju SR, Huang C, Cui H, Pan Y, Nesic M, Zhu L, Sarlah D, Mitchell DA, Zhao H. Genome mining unveils a class of ribosomal peptides with two amino termini. Nat Commun 2023; 14:1624. [PMID: 36959188 PMCID: PMC10036551 DOI: 10.1038/s41467-023-37287-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 03/09/2023] [Indexed: 03/25/2023] Open
Abstract
The era of inexpensive genome sequencing and improved bioinformatics tools has reenergized the study of natural products, including the ribosomally synthesized and post-translationally modified peptides (RiPPs). In recent years, RiPP discovery has challenged preconceptions about the scope of post-translational modification chemistry, but genome mining of new RiPP classes remains an unsolved challenge. Here, we report a RiPP class defined by an unusual (S)-N2,N2-dimethyl-1,2-propanediamine (Dmp)-modified C-terminus, which we term the daptides. Nearly 500 daptide biosynthetic gene clusters (BGCs) were identified by analyzing the RiPP Recognition Element (RRE), a common substrate-binding domain found in half of prokaryotic RiPP classes. A representative daptide BGC from Microbacterium paraoxydans DSM 15019 was selected for experimental characterization. Derived from a C-terminal threonine residue, the class-defining Dmp is installed over three steps by an oxidative decarboxylase, aminotransferase, and methyltransferase. Daptides uniquely harbor two positively charged termini, and thus we suspect this modification could aid in membrane targeting, as corroborated by hemolysis assays. Our studies further show that the oxidative decarboxylation step requires a functionally unannotated accessory protein. Fused to the C-terminus of the accessory protein is an RRE domain, which delivers the unmodified substrate peptide to the oxidative decarboxylase. This discovery of a class-defining post-translational modification in RiPPs may serve as a prototype for unveiling additional RiPP classes through genome mining.
Collapse
Affiliation(s)
- Hengqian Ren
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Shravan R Dommaraju
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Chunshuai Huang
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Haiyang Cui
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Yuwei Pan
- Department of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Marko Nesic
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Lingyang Zhu
- School of Chemical Sciences, NMR Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - David Sarlah
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Douglas A Mitchell
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
- Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
| | - Huimin Zhao
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
| |
Collapse
|
|
6
|
Ren H, Dommaraju SR, Huang C, Cui H, Pan Y, Nesic M, Zhu L, Sarlah D, Mitchell DA, Zhao H. Genome mining unveils a class of ribosomal peptides with two amino termini. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.08.531785. [PMID: 36945508 PMCID: PMC10028931 DOI: 10.1101/2023.03.08.531785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2023]
Abstract
The era of inexpensive genome sequencing and improved bioinformatics tools has reenergized the study of natural products, including the ribosomally synthesized and post-translationally modified peptides (RiPPs). In recent years, RiPP discovery has challenged preconceptions about the scope of post-translational modification chemistry, but genome mining of new RiPP classes remains an unsolved challenge. Here, we report a RiPP class defined by an unusual ( S )- N 2 , N 2 -dimethyl-1,2-propanediamine (Dmp)-modified C -terminus, which we term the daptides. Nearly 500 daptide biosynthetic gene clusters (BGCs) were identified by analyzing the RiPP Recognition Element (RRE), a common substrate-binding domain found in half of prokaryotic RiPP classes. A representative daptide BGC from Microbacterium paraoxydans DSM 15019 was selected for experimental characterization. Derived from a C -terminal threonine residue, the class-defining Dmp is installed over three steps by an oxidative decarboxylase, aminotransferase, and methyltransferase. Daptides uniquely harbor two positively charged termini, and thus we suspect this modification could aid in membrane targeting, as corroborated by hemolysis assays. Our studies further show that the oxidative decarboxylation step requires a functionally unannotated accessory protein. Fused to the C -terminus of the accessory protein is an RRE domain, which delivers the unmodified substrate peptide to the oxidative decarboxylase. This discovery of a class-defining post-translational modification in RiPPs may serve as a prototype for unveiling additional RiPP classes through genome mining.
Collapse
Affiliation(s)
- Hengqian Ren
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- These authors contributed equally to this work: Hengqian Ren, Shravan R. Dommaraju
| | - Shravan R. Dommaraju
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- These authors contributed equally to this work: Hengqian Ren, Shravan R. Dommaraju
| | - Chunshuai Huang
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Haiyang Cui
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Yuwei Pan
- Department of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Marko Nesic
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Lingyang Zhu
- School of Chemical Sciences, NMR Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - David Sarlah
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Douglas A. Mitchell
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Huimin Zhao
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| |
Collapse
|
|
7
|
Mahboob A, Senevirathne DKL, Paul P, Nabi F, Khan RH, Chaari A. An investigation into the potential action of polyphenols against human Islet Amyloid Polypeptide aggregation in type 2 diabetes. Int J Biol Macromol 2023; 225:318-350. [PMID: 36400215 DOI: 10.1016/j.ijbiomac.2022.11.038] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/24/2022] [Accepted: 11/04/2022] [Indexed: 11/17/2022]
Abstract
Type 2 diabetes (T2D), a chronic metabolic disease characterized by hyperglycemia, results in significant disease burden and financial costs globally. Whilst the majority of T2D cases seem to have a genetic basis, non-genetic modifiable and non-modifiable risk factors for T2D include obesity, diet, physical activity and lifestyle, smoking, age, ethnicity, and mental stress. In healthy individuals, insulin secretion from pancreatic islet β-cells is responsible for keeping blood glucose levels within normal ranges. T2D patients suffer from multifactorial onset of β-cell dysfunction and/or loss of β-cell mass owing to reactive oxygen species (ROS) production, mitochondrial dysfunction, autophagy, and endoplasmic reticulum (ER) stress. Most predominantly however, and the focus of this review, it is the aggregation and misfolding of human Islet Amyloid Polypeptide (hIAPP, also known as amylin), which is detrimental to β-cell function and health. Whilst hIAPP is found in healthy individuals, its misfolded version is cytotoxic and able to induce β-cell dysfunction and/or death through various mechanisms including membrane changes in β-cell causing influx of calcium ions, arresting complete granule membrane recovery and ER stress. There are several existing therapeutics for T2D. However, there is a need for alternative or adjunct therapies for T2D with milder adverse effects and greater availability. Foremost among the potential natural therapeutics are polyphenols. Extensive data from studies evaluating the potential of polyphenols to inhibit hIAPP aggregation and disassemble aggregated hIAPP are promising. Moreover, in-vivo, and in-silico studies also highlight the potential effects of polyphenols against hIAPP aggregation and mitigation of larger pathological effects of T2D. Whilst there have been some promising clinical studies on the therapeutic potential of polyphenols, extensive further clinical studies and in-vitro studies evaluating the mechanisms of action and ideal doses for many of these compounds are required. The need for these studies is made more important by the postulated link between Alzheimer's disease (AD) and T2D pathophysiology given the similar aggregation process of their respective amyloid proteins, which evokes thoughts of cross-reactive polyphenols which can be effective for both AD and T2D patients.
Collapse
Affiliation(s)
- Anns Mahboob
- Premedical Division Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | | | - Pradipta Paul
- Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | - Faisal Nabi
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202001, India
| | - Rizwan Hasan Khan
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202001, India
| | - Ali Chaari
- Premedical Division Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar.
| |
Collapse
|
|
8
|
Miller ME, Li MH, Baghai A, Peetz VH, Zhyvoloup A, Raleigh DP. Analysis of Sheep and Goat IAPP Provides Insight into IAPP Amyloidogenicity and Cytotoxicity. Biochemistry 2022; 61:2531-2545. [PMID: 36286531 PMCID: PMC11132794 DOI: 10.1021/acs.biochem.2c00470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Human islet amyloid polypeptide (hIAPP) plays a role in glucose regulation but forms pancreatic amyloid deposits in type 2 diabetes, and that process contributes to β-cell dysfunction. Not all species develop diabetes, and not all secrete an IAPP that is amyloidogenic in vitro under normal conditions, a perfect correlation currently exists between both. Studies of IAPPs from such organisms can provide clues about the high amyloidogenicity of hIAPP and can inform the design of soluble analogues of hIAPP. Sheep and goat IAPP are among the most divergent from hIAPP, with 13 and 11 substitutions, respectively, including an unusual Tyr to His substitution at the C-terminus. The properties of sheep and goat IAPP were examined in solution and in the presence of anionic vesicles, resulting in no observed amyloid formation, even at increased concentrations. Furthermore, both peptides are considerably less toxic to cultured β-cells than hIAPP. The effect of the Y37H replacements was studied in the context of hIAPP, as was a Y37R substitution. Buffer- and salt-dependent effects were observed. There was little impact on the time to form amyloid in phosphate-buffered saline; however, a significant deceleration was observed in Tris buffer, and amyloid formation was slower in the absence of added salt. The Y37H substitution had little impact on toxicity, while the Y37R replacement led to a 30% decrease in toxicity compared with that of hIAPP. The implications for the amyloidogenicity of hIAPP and the design of soluble analogues of the human peptide are discussed.
Collapse
Affiliation(s)
- Matthew E.T. Miller
- Department of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States
| | - Ming-Hao Li
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, New York 11790, United States
| | - Aria Baghai
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
| | - Vincent H. Peetz
- Department of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States
| | - Alexander Zhyvoloup
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
| | - Daniel P. Raleigh
- Department of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States
- Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, New York 11790, United States
- Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States
| |
Collapse
|
|
9
|
Dicke SS, Maj M, Fields CR, Zanni MT. Metastable intermediate during hIAPP aggregation catalyzed by membranes as detected with 2D IR spectroscopy. RSC Chem Biol 2022; 3:931-940. [PMID: 35866164 PMCID: PMC9257649 DOI: 10.1039/d2cb00028h] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/24/2022] [Indexed: 11/26/2022] Open
Abstract
The aggregation of human islet amyloid polypeptide (hIAPP) into amyloid fibrils involves formation of oligomeric intermediates that are thought to be the cytotoxic species responsible for β-cell dysfunction in type 2 diabetes. hIAPP oligomers permeating or disrupting the cellular membrane may be one mechanism of toxicity and so measuring the structural kinetics of aggregation in the presence of membranes is of much interest. In this study, we use 2D IR spectroscopy and 13C18O isotope labeling to study the secondary structure of the oligomeric intermediates formed in solution and in the presence of phospholipid vesicles at sites L12A13, L16V17, G24A25 and V32G33. Pairs of labels monitor the couplings between associated polypeptides and the dihedral angles between adjacent residues. In solution, the L12A13 residues form an oligomeric β-sheet in addition to an α-helix whereas with the phospholipid vesicles they are α-helical throughout the aggregation process. In both solution and with DOPC vesicles, L16V17 and V32G33 have disordered structures until fibrils are formed. Similarly, under both conditions, G24A25 exhibits 3-state kinetics, created by an oligomeric intermediate with a well-defined β-sheet structure. Amyloid fibril formation is often thought to involve intermediates with exceedingly low populations that are difficult to detect experimentally. These experiments establish that amyloid fibril formation of hIAPP when catalyzed by membranes includes a metastable intermediate and that this intermediate has a similar structure at G24A25 in the FGAIL region as the corresponding intermediate in solution, thought to be the toxic species. 2D IR and 13C18O isotope labeling establish that amyloid formation of hIAPP catalyzed by membranes includes a metastable intermediate with a similar structure at G24A25 in the FGAIL region as the corresponding intermediate in solution.![]()
Collapse
Affiliation(s)
- Sidney S Dicke
- Department of Chemistry, University of Wisconsin-Madison 1101 University Avenue Madison WI 53706 USA
| | - Michał Maj
- Department of Chemistry, University of Wisconsin-Madison 1101 University Avenue Madison WI 53706 USA .,Formally at Department of Chemistry, University of Wisconsin-Madison 1101 University Avenue Madison WI 53706 USA
| | - Caitlyn R Fields
- Department of Chemistry, University of Wisconsin-Madison 1101 University Avenue Madison WI 53706 USA
| | - Martin T Zanni
- Department of Chemistry, University of Wisconsin-Madison 1101 University Avenue Madison WI 53706 USA
| |
Collapse
|
|
10
|
Tsaryk I, Pashkovska N. Relationship between the Level of Amylinemia and Albuminuria Categories in Patients with Latent Autoimmune Diabetes in Adults. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.9802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: β-cells of islets of Langerhans produce not only insulin but another hormone – amylin, whose role in the development and progression of chronic kidney disease (CKD) in patients with diabetes mellitus (DM) is not known for certain.
AIM: The aim of the study was to determine the relationship between amylinemia and albuminuria categories in patients with latent autoimmune diabetes in adults (LADA) and CKD.
METHODS: 89 patients with DM and CKD were examined, as well as 15 representatives of the control group. The patients were divided into three groups by the types of DM: 36 patients with LADA, 25 patients with classical type 1 diabetes mellitus (T1D), and 28 patients with type 2 diabetes (T2D). Serum amylin levels were measured using the enzyme-linked immunosorbent assay (ELISA) method.
RESULTS: In the group of patients with LADA, the amylin content was 9.0 times higher than in control (p < 0.01) and 6.8 times higher compared to classical T1D (p < 0.01); at the same time, it was 17.3% lower than in T2D group (p < 0.05). In patients with T1D, the level of amylinemia did not change, whereas in T2D group it was 10.8 times significantly higher compared to the control and 8.3 times higher than in the group of patients with classical T1D. The highest indicator was registered in patients with LADA2 phenotype. The level of amylin was increasing in proportion to the categories of albuminuria. Positive correlations were found between the content of amylin and insulin, C-peptide, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index and creatinine.
CONCLUSION: Serum amylin level significantly increases progrediently to the albuminuria categories in patients with LADA (especially in LADA2 phenotype) and T2D.
Collapse
|
|
11
|
Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions. BIOCHIMICA ET BIOPHYSICA ACTA. PROTEINS AND PROTEOMICS 2022; 1870:140772. [PMID: 35307557 DOI: 10.1016/j.bbapap.2022.140772] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/09/2022] [Accepted: 03/13/2022] [Indexed: 01/29/2023]
Abstract
Type 2 Diabetes is a major public health threat, and its prevalence is increasing worldwide. The abnormal accumulation of islet amyloid polypeptide (IAPP) in pancreatic β-cells is associated with the onset of the disease. Therefore, the design of small molecules able to inhibit IAPP aggregation represents a promising strategy in the development of new therapies. Here we employ in vitro, biophysical, and computational methods to inspect the ability of Silybin A and Silybin B, two natural diastereoisomers extracted from milk thistle, to interfere with the toxic self-assembly of human IAPP (hIAPP). We show that Silybin B inhibits amyloid aggregation and protects INS-1 cells from hIAPP toxicity more than Silybin A. Molecular dynamics simulations revealed that the higher efficiency of Silybin B is ascribable to its interactions with precise hIAPP regions that are notoriously involved in hIAPP self-assembly i.e., the S20-S29 amyloidogenic core, H18, the N-terminal domain, and N35. These results highlight the importance of stereospecific ligand-peptide interactions in regulating amyloid aggregation and provide a blueprint for future studies aimed at designing Silybin derivatives with enhanced drug-like properties.
Collapse
|
|
12
|
Gupta A, Dey S, Bhowmik D, Maiti S. Coexisting Ordered and Disordered Membrane Phases Have Distinct Modes of Interaction with Disease-Associated Oligomers. J Phys Chem B 2022; 126:1016-1023. [PMID: 35104126 DOI: 10.1021/acs.jpcb.1c09421] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Ordered membrane domains are thought to influence the attachment and insertion of toxic amyloid oligomers, and consequently, their toxicity. However, if and how the molecular aspects of this interaction depend on the membrane order is poorly understood. Here we measure the affinity, location, and degree of insertion of the small oligomers of hIAPP (human Islet Amyloid Polypeptide, associated with Type II diabetes) at near-physiological concentrations to adjacent domains of a biphasic lipid bilayer. Using simultaneous atomic force, confocal and fluorescence lifetime microscopy (AFM-FLIM), we find that hIAPP oligomers have a nearly 8-fold higher affinity to the disordered domains over the ordered domains. To probe whether this difference indicates different modes of interaction, we measure the change of lifetime of peptide-attached fluorescent labels induced by soluble fluorescence quenchers and also measure the kinetics of localized photobleaching. We find that in the raft-like ordered domains, the oligomers primarily lie on the aqueous interface with limited membrane penetration. However, in the neighboring disordered domains, their C-termini penetrate deeper into the lipid bilayer. We conclude that local membrane order determines not only the affinity but also the mode of interaction of amyloid oligomers, which may have significant implications for disease mechanisms.
Collapse
Affiliation(s)
- Ankur Gupta
- Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India
| | - Simli Dey
- Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India
| | - Debanjan Bhowmik
- Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India
| | - Sudipta Maiti
- Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India
| |
Collapse
|
|
13
|
Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes. Nutrients 2021; 13:nu13124285. [PMID: 34959837 PMCID: PMC8705976 DOI: 10.3390/nu13124285] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.
Collapse
|
|
14
|
Sarkar A, Nazir A. Carrying Excess Baggage Can Slowdown Life: Protein Clearance Machineries That Go Awry During Aging and the Relevance of Maintaining Them. Mol Neurobiol 2021; 59:821-840. [PMID: 34792731 DOI: 10.1007/s12035-021-02640-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/05/2021] [Indexed: 01/07/2023]
Abstract
Cellular homeostasis is maintained by rapid and systematic cleansing of aberrant and aggregated proteins within cells. Neurodegenerative diseases (NDs) especially Parkinson's and Alzheimer's disease are known to be associated with multiple factors, most important being impaired clearance of aggregates, resulting in the accumulation of specific aggregated protein in the brain. Protein quality control (PQC) of proteostasis network comprises proteolytic machineries and chaperones along with their regulators to ensure precise operation and maintenance of proteostasis. Such regulatory factors coordinate among each other multiple functional aspects related to proteins, including their synthesis, folding, transport, and degradation. During aging due to inevitable endogenous and external stresses, sustaining a proteome balance is a challenging task. Such stresses decline the capacity of the proteostasis network compromising the proteome integrity, affecting the fundamental physiological processes including reproductive fitness of the organism. This review focuses on highlighting proteome-wide changes during aging and the strategies for proteostasis improvements. The possibility of augmenting the proteostasis network either via genetic or pharmacological interventions may be a promising strategy towards delaying age-associated pathological consequences due to proteome disbalance, thus promoting healthy aging and prolonged longevity.
Collapse
Affiliation(s)
- Arunabh Sarkar
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India
| | - Aamir Nazir
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India.
| |
Collapse
|
|
15
|
Behl T, Arora A, Sehgal A, Singh S, Sharma N, Bhatia S, Al-Harrasi A, Bungau S, Mostafavi E. Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 21:542-556. [PMID: 34758720 DOI: 10.2174/1871527320666211110115257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/25/2021] [Accepted: 09/15/2021] [Indexed: 11/22/2022]
Abstract
Diabetes mellitus is a major metabolic disorder that has now emerged as an epidemic, and it affects the brain through an array of pathways. Diabetes mellitus patients can develop pathological changes in the brain, which eventually take the shape of mild cognitive impairment progressing to Alzheimer's Disease. A number of preclinical and clinical studies demonstrate this fact, and it comes out to be those molecular pathways such as amyloidogenesis, oxidative stress, inflammation, and impaired insulin signaling are identical in diabetes mellitus and dementia. However, the critical player involved in the vicious cycle of diabetes mellitus and dementia is insulin, whose signaling, when impaired in diabetes mellitus (both type 1 and 2), leads to a decline in cognition, although other pathways are also essential contributors. Moreover, it is not only that diabetes mellitus patients indicate cognitive decline at a later stage; many Alzheimer's Disease patients also reflect symptoms of diabetes mellitus, thus creating a vicious cycle inculcating a web of complex molecular mechanisms and hence categorizing Alzheimer's Disease as 'brain diabetes'. Thus, it is practical to suggest that anti-diabetic drugs are beneficial in Alzheimer's Disease; but only smaller trials, not the larger ones, have showcased positive outcomes mainly because of the late onset of therapy. Therefore, it is extremely important to develop more of such molecules that target insulin in dementia patients along with such methods that diagnose impaired insulin signaling and the associated cognitive decline so that early therapy may be initiated and the progression of the disease be prevented.
Collapse
Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Arpita Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Haryana. India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa. Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea. Romania
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA. United States
| |
Collapse
|
|
16
|
Pathak BK, Dey S, Mozumder S, Sengupta J. The role of membranes in function and dysfunction of intrinsically disordered amyloidogenic proteins. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 128:397-434. [PMID: 35034725 DOI: 10.1016/bs.apcsb.2021.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Membrane-protein interactions play a major role in human physiology as well as in diseases pathology. Interaction of a protein with the membrane was previously thought to be dependent on well-defined three-dimensional structure of the protein. In recent decades, however, it has become evident that a large fraction of the proteome, particularly in eukaryotes, stays disordered in solution and these proteins are termed as intrinsically disordered proteins (IDPs). Also, a vast majority of human proteomes have been reported to contain substantially long disordered regions, called intrinsically disordered regions (IDRs), in addition to the structurally ordered regions. IDPs exist in an ensemble of conformations and the conformational flexibility enables IDPs to achieve functional diversity. IDPs (and IDRs) are found to be important players in cell signaling, where biological membranes act as anchors for signaling cascades. Therefore, IDPs modulate the membrane architectures, at the same time membrane composition also affects the binding of IDPs. Because of intrinsic disorders, misfolding of IDPs often leads to formation of oligomers, protofibrils and mature fibrils through progressive self-association. Accumulation of amyloid-like aggregates of some of the IDPs is a known causative agent for numerous diseases. In this chapter we highlight recent advances in understanding membrane interactions of some of the intrinsically disordered proteins involved in the pathogenesis of human diseases.
Collapse
Affiliation(s)
- Bani Kumar Pathak
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India
| | - Sandip Dey
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India
| | - Sukanya Mozumder
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Jayati Sengupta
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
| |
Collapse
|
|
17
|
Marmentini C, Branco RCS, Boschero AC, Kurauti MA. Islet amyloid toxicity: From genesis to counteracting mechanisms. J Cell Physiol 2021; 237:1119-1142. [PMID: 34636428 DOI: 10.1002/jcp.30600] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 09/09/2021] [Accepted: 10/01/2021] [Indexed: 11/11/2022]
Abstract
Islet amyloid polypeptide (IAPP or amylin) is a hormone co-secreted with insulin by pancreatic β-cells and is the major component of islet amyloid. Islet amyloid is found in the pancreas of patients with type 2 diabetes (T2D) and may be involved in β-cell dysfunction and death, observed in this disease. Thus, investigating the aspects related to amyloid formation is relevant to the development of strategies towards β-cell protection. In this sense, IAPP misprocessing, IAPP overproduction, and disturbances in intra- and extracellular environments seem to be decisive for IAPP to form islet amyloid. Islet amyloid toxicity in β-cells may be triggered in intra- and/or extracellular sites by membrane damage, endoplasmic reticulum stress, autophagy disruption, mitochondrial dysfunction, inflammation, and apoptosis. Importantly, different approaches have been suggested to prevent islet amyloid cytotoxicity, from inhibition of IAPP aggregation to attenuation of cell death mechanisms. Such approaches have improved β-cell function and prevented the development of hyperglycemia in animals. Therefore, counteracting islet amyloid may be a promising therapy for T2D treatment.
Collapse
Affiliation(s)
- Carine Marmentini
- Laboratory of Endocrine Pancreas and Metabolism, Obesity and Comorbidities Research Center (OCRC), University of Campinas (UNICAMP), Campinas, Brazil
| | - Renato C S Branco
- Laboratory of Endocrine Pancreas and Metabolism, Obesity and Comorbidities Research Center (OCRC), University of Campinas (UNICAMP), Campinas, Brazil
| | - Antonio C Boschero
- Laboratory of Endocrine Pancreas and Metabolism, Obesity and Comorbidities Research Center (OCRC), University of Campinas (UNICAMP), Campinas, Brazil
| | - Mirian A Kurauti
- Laboratory of Endocrine Pancreas and Metabolism, Obesity and Comorbidities Research Center (OCRC), University of Campinas (UNICAMP), Campinas, Brazil.,Department of Physiological Sciences, Biological Sciences Center, State University of Maringa (UEM), Maringa, Brazil
| |
Collapse
|
|
18
|
Sepehri A, Nepal B, Lazaridis T. Distinct Modes of Action of IAPP Oligomers on Membranes. J Chem Inf Model 2021; 61:4645-4655. [PMID: 34499498 DOI: 10.1021/acs.jcim.1c00767] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Islet amyloid polypeptide (IAPP, also known as amylin) is a peptide hormone that is co-secreted with insulin by pancreatic β-cells and forms amyloid aggregates in type II diabetes. Various lines of evidence indicate that oligomers of this peptide may induce toxicity by disrupting or forming pores in cell membranes, but the structure of these pores is unknown. Here, we create models of pores for both helical and β-structured peptides using implicit membrane modeling and test their stability using multimicrosecond all-atom simulations. We find that the helical peptides behave similarly to antimicrobial peptides; they remain stably inserted in a highly tilted or partially unfolded configuration creating a narrow water channel. Parallel helix orientation creates a somewhat larger pore. An octameric β barrel of parallel β-hairpins is highly stable in the membrane, whereas the corresponding barrel made of antiparallel hairpins is not. We propose that certain experiments probe the helical pore state while others probe the β-structured pore state; this provides a possible explanation for lack of correlation that is sometimes observed between in vivo toxicity and in vitro liposome permeabilization experiments.
Collapse
Affiliation(s)
- Aliasghar Sepehri
- Department of Chemistry, City College of New York, New York, New York 10031, United States
| | - Binod Nepal
- Department of Chemistry, City College of New York, New York, New York 10031, United States
| | - Themis Lazaridis
- Department of Chemistry, City College of New York, New York, New York 10031, United States.,Graduate Programs in Chemistry, Biochemistry, and Physics, The Graduate Center, City University of New York, New York, New York, New York 10016, United States
| |
Collapse
|
|
19
|
Salimi A, Chatterjee S, Yong Lee J. Histidine Tautomerism Driving Human Islet Amyloid Polypeptide Aggregation in the Early Stages of Diabetes Mellitus Progression: Insight at the Atomistic Level. Chem Asian J 2021; 16:2453-2462. [PMID: 34231327 DOI: 10.1002/asia.202100641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/04/2021] [Indexed: 12/19/2022]
Abstract
Early oligomerization of human islet amyloid polypeptide (hIAPP), which is accountable for β-cell death, has been implicated in the progression of type 2 diabetes mellitus. Some researches have shown the connection between hIAPP and Alzheimer's disease as well. However, the mechanism of peptide accumulation and associated cytotoxicity remains unclear. Due to the unique properties and significant role of histidine in protein sequences, here for the first time, the tautomeric effect of histidine at the early stages of amylin misfolding was investigated via molecular dynamics simulations. Considering Tau and Pi tautomeric forms of histidine (Tau and Pi tautomers are denoted as ϵ and δ, respectively), simulations were performed on two possible isomers of amylin. Our analysis revealed a higher probability of transient α-helix generation in the δ isomer in monomeric form. In dimeric forms, the δδ and δϵ conformations showed an elevated amount of α-helix and lower coil in comparison to the ϵϵ dimer. Due to the significant role of α-helix in membrane disruption and transition to β-sheet structure, these results may imply a noticeable contribution of the δ isomer and the δδ and δϵ dimers rather than ϵ and ϵϵ conformations in the early stages of diabetes initiation. Our results may aid in elucidating the hIAPP self-association process in the etiology of amyloidosis.
Collapse
Affiliation(s)
- Abbas Salimi
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, South Korea
| | | | - Jin Yong Lee
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, South Korea
| |
Collapse
|
|
20
|
Babych M, Nguyen PT, Côté-Cyr M, Kihal N, Quittot N, Golizeh M, Sleno L, Bourgault S. Site-Specific Alkylation of the Islet Amyloid Polypeptide Accelerates Self-Assembly and Potentiates Perturbation of Lipid Membranes. Biochemistry 2021; 60:2285-2299. [PMID: 34264642 DOI: 10.1021/acs.biochem.1c00308] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The accumulation of insoluble amyloids in the pancreatic islets is a pathological hallmark of type II diabetes and correlates closely with the loss of β-cell mass. The predominant component of these amyloid deposits is the islet amyloid polypeptide (IAPP). The factors contributing to the conversion of IAPP from a monomeric bioactive peptide hormone into insoluble amyloid fibrils remain partially elusive. In this study, we investigated the effect of the oxidative non-enzymatic post-translational modification induced by the reactive metabolite 4-hydroxynonenal (HNE) on IAPP aggregation and cytotoxicity. Incubation of IAPP with exogenous HNE accelerated its self-assembly into β-sheet fibrils and led to the formation of a Michael adduct on the His-18 side chain. To model this covalent modification, the imidazole N(π) position of histidine was alkylated using a close analogue of HNE, the octyl chain. IAPP lipidated at His-18 showed a hastened random coil-to-β-sheet conformational conversion into fibrillar assemblies with a distinct morphology, a low level of binding to thioflavin T, and a high surface hydrophobicity. Introducing an octyl chain on His-18 enhanced the ability of the peptide to perturb synthetic lipid vesicles, to permeabilize the plasma membrane, and to induce the death of pancreatic β-cells. Alkylated IAPP triggered the self-assembly of unmodified IAPP by prompting primary nucleation and increased its capacity to perturb the plasma membrane, indicating that only a small proportion of the modified peptide is necessary to shift the balance toward the formation of proteotoxic species. This study underlines the importance of studying IAPP post-translational modifications induced by oxidative metabolites in the context of pancreatic amyloids.
Collapse
Affiliation(s)
- Margaryta Babych
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Phuong Trang Nguyen
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Mélanie Côté-Cyr
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Nadjib Kihal
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Noé Quittot
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Makan Golizeh
- Department of Mathematical and Physical Sciences, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada
| | - Lekha Sleno
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada
| | - Steve Bourgault
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| |
Collapse
|
|
21
|
Marvastizadeh N, Dabirmanesh B, Sajedi RH, Khajeh K. Anti-amyloidogenic effect of artemin on α-synuclein. Biol Chem 2021; 401:1143-1151. [PMID: 32673279 DOI: 10.1515/hsz-2019-0446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 04/20/2020] [Indexed: 11/15/2022]
Abstract
α-Synuclein fibrillation is now regarded as a major pathogenic process in Parkinson's disease and its proteinaceous deposits are also detected in other neurological disorders including Alzheimer's disease. Therefore anti-amyloidegenic compounds may delay or prevent the progression of synucleinopathies disease. Molecular chaperones are group of proteins which mediate correct folding of proteins by preventing unsuitable interactions which may lead to aggregation. The objective of this study was to investigate the anti-amyloidogenic effect of molecular chaperone artemin on α-synuclein. As the concentration of artemin was increased up to 4 μg/ml, a decrease in fibril formation of α-synuclein was observed using thioflavin T (ThT) fluorescence and congo red (CR) assay. Transmission electron microscopy (TEM) images also demonstrated a reduction in fibrils in the presence of artemin. The secondary structure of α-synuclein was similar to its native form prior to fibrillation when incubated with artemin. A cell-based assay has shown that artemin inhibits α-synuclein aggregation and reduce cytotoxicity, apoptosis and reactive oxygen species (ROS) production. Our results revealed that artemin has efficient chaperon activity for preventing α-synuclein fibril formation and toxicity.
Collapse
Affiliation(s)
- Narges Marvastizadeh
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
| | - Bahareh Dabirmanesh
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
| | - Reza H Sajedi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
| | - Khosro Khajeh
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
| |
Collapse
|
|
22
|
Ilyinsky NS, Nesterov SV, Shestoperova EI, Fonin AV, Uversky VN, Gordeliy VI. On the Role of Normal Aging Processes in the Onset and Pathogenesis of Diseases Associated with the Abnormal Accumulation of Protein Aggregates. BIOCHEMISTRY (MOSCOW) 2021; 86:275-289. [PMID: 33838629 DOI: 10.1134/s0006297921030056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Aging is a prime systemic cause of various age-related diseases, in particular, proteinopathies. In fact, most diseases associated with protein misfolding are sporadic, and their incidence increases with aging. This review examines the process of protein aggregate formation, the toxicity of such aggregates, the organization of cellular systems involved in proteostasis, and the impact of protein aggregates on important cellular processes leading to proteinopathies. We also analyze how manifestations of aging (mitochondrial dysfunction, dysfunction of signaling systems, changes in the genome and epigenome) facilitate pathogenesis of various proteinopathies either directly, by increasing the propensity of key proteins for aggregation, or indirectly, through dysregulation of stress responses. Such analysis might help in outlining approaches for treating proteinopathies and extending healthy longevity.
Collapse
Affiliation(s)
- Nikolay S Ilyinsky
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.
| | - Semen V Nesterov
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.,Institute of Cytochemistry and Molecular Pharmacology, Moscow, 115404, Russia
| | - Elizaveta I Shestoperova
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia
| | - Alexander V Fonin
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.,Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, 194064, Russia
| | - Vladimir N Uversky
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.,Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Valentin I Gordeliy
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.,Forschungszentrum Juelich, Juelich, 52428, Germany.,Institut de Biologie Structurale, Grenoble, 38000, France
| |
Collapse
|
|
23
|
Khemtemourian L, Antoniciello F, Sahoo BR, Decossas M, Lecomte S, Ramamoorthy A. Investigation of the effects of two major secretory granules components, insulin and zinc, on human-IAPP amyloid aggregation and membrane damage. Chem Phys Lipids 2021; 237:105083. [PMID: 33887213 DOI: 10.1016/j.chemphyslip.2021.105083] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/11/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023]
Abstract
Human islet amyloid polypeptide (hIAPP) is a highly amyloidogenic peptide found in pancreatic islets of type-2 diabetes (T2D) patients. Under certain conditions, hIAPP is able to form amyloid fibrils that play a role in the progression of T2D. hIAPP is synthesized in the β-cell of the pancreas and stored in the secretory granules before being released into the extracellular compartment. It has been suggested that natural stabilizing agents, such as insulin or zinc present in the secretory granules with hIAPP could prevent hIAPP fibril formation. The difference in the amino acid sequences of IAPP among species strongly correlates with amyloidogenicity and toxicity. The residue histidine at position 18 is known to be important in modulating the fibril formation, membrane leakage and toxicity. In this study, we have synthesized four analogues of hIAPP (H18R-IAPP, H18K-IAPP, H18A-IAPP and H18E-IAPP) and characterized their aggregation with either insulin or zinc in order to determine the effect of the residue-18 on the insulin-IAPP and zinc-IAPP interactions using a variety of biophysical experiments including thioflavin-T fluorescence, transmission electron microscopy imaging, circular dichroism, and NMR spectroscopy. We show that insulin reduced hIAPP fibril formation both in solution and in the presence of membrane and hIAPP-membrane damage and that the interactions are somewhat mediated by the residue-18. In addition, our results reveal that zinc affects the process of hIAPP fibril formation in solution but not in the presence of membrane. Our results indicate that the nature of the residue-18 is important for zinc binding. Based on this observation, we hypothesize that zinc binds to the residues in the N-terminal region of hIAPP, which is not accessible in the presence of membrane due to its strong interaction with lipids.
Collapse
Affiliation(s)
| | | | - Bikash R Sahoo
- Biophysics Program, Department of Chemistry, Biomedical Engineering, and Macromolecular Science and Engineering, The University of Michigan, Ann Arbor, MI 48109-1055, USA
| | - Marion Decossas
- CBMN, CNRS UMR 5248, IPB, Univ. Bordeaux, F-33600 Pessac, France
| | - Sophie Lecomte
- CBMN, CNRS UMR 5248, IPB, Univ. Bordeaux, F-33600 Pessac, France
| | - Ayyalusamy Ramamoorthy
- Biophysics Program, Department of Chemistry, Biomedical Engineering, and Macromolecular Science and Engineering, The University of Michigan, Ann Arbor, MI 48109-1055, USA.
| |
Collapse
|
|
24
|
Abstract
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.
Collapse
|
|
25
|
Milardi D, Gazit E, Radford SE, Xu Y, Gallardo RU, Caflisch A, Westermark GT, Westermark P, Rosa CL, Ramamoorthy A. Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes. Chem Rev 2021; 121:1845-1893. [PMID: 33427465 PMCID: PMC10317076 DOI: 10.1021/acs.chemrev.0c00981] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin, and zinc on the mechanism of aggregation of hIAPP. The challenges posed by the transient nature of amyloid oligomers, their structural heterogeneity, and the complex nature of their interaction with lipid membranes have resulted in the development of a wide range of biophysical and chemical approaches to characterize the aggregation process. While the cellular processes and factors activating hIAPP-mediated cytotoxicity are still not clear, it has recently been suggested that its impaired turnover and cellular processing by proteasome and autophagy may contribute significantly toward toxic hIAPP accumulation and, eventually, β-cell death. Therefore, studies focusing on the restoration of hIAPP proteostasis may represent a promising arena for the design of effective therapies. In this review we discuss the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.
Collapse
Affiliation(s)
- Danilo Milardi
- Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via P. Gaifami 18, 95126 Catania, Italy
| | - Ehud Gazit
- Department of Molecular Microbiology and Biotechnology, The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Sheena E Radford
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Yong Xu
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Rodrigo U Gallardo
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Amedeo Caflisch
- Department of Biochemistry, University of Zürich, Zürich CH-8057, Switzerland
| | - Gunilla T Westermark
- Department of Medical Cell Biology, Uppsala University, SE-751 23 Uppsala, Sweden
| | - Per Westermark
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden
| | - Carmelo La Rosa
- Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
| | - Ayyalusamy Ramamoorthy
- Biophysics, Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 41809-1055, United States
| |
Collapse
|
|
26
|
Kalita S, Kalita S, Paul A, Shah M, Kumar S, Mandal B. Site-specific single point mutation by anthranilic acid in hIAPP 8-37 enhances anti-amyloidogenic activity. RSC Chem Biol 2021; 2:266-273. [PMID: 34458787 PMCID: PMC8341151 DOI: 10.1039/d0cb00178c] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 12/24/2020] [Indexed: 12/01/2022] Open
Abstract
Amylin or hIAPP, together with insulin, plays a significant role in glucose metabolism. However, it undergoes β-sheet rich amyloid formation associated with pancreatic β-cell dysfunction leading to type-2 diabetes (T2D). Recent studies suggest that restricting β-sheet formation in it may halt amyloid formation, which may limit the risk for the disease. Several peptide-based inhibitors have been reported to prevent aggregation. However, most of them have limitations, including low binding efficiency, active only at higher doses, poor solubility, and proteolytic degradation. Insertion of non-coded amino acids renders proteolytically stable peptides. We incorporated a structurally rigid β-amino acid, Anthranilic acid (Ant), at different sites within the central hydrophobic region of hIAPP and developed two singly mutated hIAPP8–37 peptidomimetics. These peptidomimetics inhibited the amyloid formation of hIAPP substantially even at low concentration, as evident from in vitro ThT, CD, FT-IR, TEM, and Congo red staining birefringence results. These peptidomimetics also disrupted the preformed aggregates formed by hIAPP into non-toxic species. These β-amino acid-based peptidomimetics can be an attractive scaffold for therapeutic design towards T2D or other protein misfolding diseases. β-Amino acid based peptidomimetics are attractive scaffolds for therapeutics design towards T2D. They prevent amyloid formation of hIAPP by forming non-fibrillar non-toxic aggregates.![]()
Collapse
Affiliation(s)
- Sourav Kalita
- Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati Assam-781039 India
| | - Sujan Kalita
- Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati Assam-781039 India
| | - Ashim Paul
- Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati Assam-781039 India
| | - Manisha Shah
- Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati Assam-781039 India
| | - Sachin Kumar
- Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati Assam-781039 India
| | - Bhubaneswar Mandal
- Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati Assam-781039 India
| |
Collapse
|
|
27
|
Farrugia F, Aquilina A, Vassallo J, Pace NP. Bisphenol A and Type 2 Diabetes Mellitus: A Review of Epidemiologic, Functional, and Early Life Factors. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:E716. [PMID: 33467592 PMCID: PMC7830729 DOI: 10.3390/ijerph18020716] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/10/2021] [Accepted: 01/13/2021] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance and eventual pancreatic β-cell dysfunction, resulting in persistent high blood glucose levels. Endocrine disrupting chemicals (EDCs) such as bisphenol A (BPA) are currently under scrutiny as they are implicated in the development of metabolic diseases, including T2DM. BPA is a pervasive EDC, being the main constituent of polycarbonate plastics. It can enter the human body by ingestion, through the skin, and cross from mother to offspring via the placenta or breast milk. BPA is a xenoestrogen that alters various aspects of beta cell metabolism via the modulation of oestrogen receptor signalling. In vivo and in vitro models reveal that varying concentrations of BPA disrupt glucose homeostasis and pancreatic β-cell function by altering gene expression and mitochondrial morphology. BPA also plays a role in the development of insulin resistance and has been linked to long-term adverse metabolic effects following foetal and perinatal exposure. Several epidemiological studies reveal a significant association between BPA and the development of insulin resistance and impaired glucose homeostasis, although conflicting findings driven by multiple confounding factors have been reported. In this review, the main findings of epidemiological and functional studies are summarised and compared, and their respective strengths and limitations are discussed. Further research is essential for understanding the exact mechanism of BPA action in various tissues and the extent of its effects on humans at environmentally relevant doses.
Collapse
Affiliation(s)
- Francesca Farrugia
- Department of Physiology and Biochemistry, University of Malta, MSD 2080 Msida, Malta; (F.F.); (A.A.); (J.V.)
| | - Alexia Aquilina
- Department of Physiology and Biochemistry, University of Malta, MSD 2080 Msida, Malta; (F.F.); (A.A.); (J.V.)
| | - Josanne Vassallo
- Department of Physiology and Biochemistry, University of Malta, MSD 2080 Msida, Malta; (F.F.); (A.A.); (J.V.)
- Centre for Molecular Medicine and Biobanking, University of Malta, MSD 2080 Msida, Malt
| | - Nikolai Paul Pace
- Department of Physiology and Biochemistry, University of Malta, MSD 2080 Msida, Malta; (F.F.); (A.A.); (J.V.)
- Centre for Molecular Medicine and Biobanking, University of Malta, MSD 2080 Msida, Malt
| |
Collapse
|
|
28
|
Wang Y, Meng F, Lu T, Wang C, Li F. Regulation of divalent metal ions to the aggregation and membrane damage of human islet amyloid polypeptide oligomers. RSC Adv 2021; 11:12815-12825. [PMID: 35423832 PMCID: PMC8697352 DOI: 10.1039/d1ra00354b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/21/2021] [Indexed: 11/21/2022] Open
Abstract
The accumulation of human islet amyloid polypeptide (hIAPP) on the surface of pancreatic β cells is closely related to the death of the cells. Divalent metal ions play a significant role in the cytotoxicity of hIAPP. In this study, we examined the roles played by the divalent metal ions of zinc, copper and calcium in the aggregation of both hIAPP18-27 fragment and full-length hIAPP and the ability of their oligomers to damage the membrane of POPC/POPG 4 : 1 LUVs using the ThT fluorescence, TEM, AFM, CD, ANS binding fluorescence and dye leakage experiments. We prepared metal-free and metal-associated oligomers that are similar in size and aggregate slowly using the short peptide and confirmed that the ability of the peptide oligomers to damage the lipid membrane is reduced by the binding to the metal ions, which is closely linked to the reducing hydrophobic exposure of the metal-associated oligomers. The study on the full-length hIAPP showed that the observed membrane damage induced by hIAPP oligomers is either mitigated at a peptide-to-metal ratio of 1 : 0.33 or aggravated at a peptide-to-metal ratio of 1 : 1 in the presence of Zn(ii) and Cu(ii), while the surface hydrophobicity of hIAPP oligomers was reduced at both peptide-to-metal ratios. The observed results of the membrane damage were attributed to the counteraction between a decrease in the disruptive ability of metal-associated oligomer species and an increase in the quantity of oligomers promoted by the binding of the metal ions to hIAPP oligomers. The former could play a predominant role in reducing the membrane damage at a peptide-to-metal ratio of 1 : 0.33, while the latter could play a predominant role in enhancing the membrane damage at a peptide-to-metal ratio of 1 : 1. This study shows that an enhanced membrane damage could be caused by the oligomer species with a decreased instead of an increased disruptive ability, given that the abundance of the oligomer species is high enough. Their is a counteraction between a decrease in the disruptive ability of metal-associated oligomer species and an increase in the quantity of oligomers promoted by the metal binding in the activity of hIAPP induced membrane damage.![]()
Collapse
Affiliation(s)
- Yajie Wang
- State Key Laboratory of Supramolecular Structure and Materials
- Jilin University
- Changchun 130012
- P. R. China
| | - Feihong Meng
- State Key Laboratory of Supramolecular Structure and Materials
- Jilin University
- Changchun 130012
- P. R. China
| | - Tong Lu
- State Key Laboratory of Supramolecular Structure and Materials
- Jilin University
- Changchun 130012
- P. R. China
| | - Chunyun Wang
- State Key Laboratory of Supramolecular Structure and Materials
- Jilin University
- Changchun 130012
- P. R. China
| | - Fei Li
- State Key Laboratory of Supramolecular Structure and Materials
- Jilin University
- Changchun 130012
- P. R. China
| |
Collapse
|
|
29
|
Rozniakowski K, Galecki K, Wietrzyk J, Filip-Psurska B, Fraczyk J, Kaminski ZJ, Kolesinska B. N-Methylated Analogs of hIAPP Fragments 18-22, 23-27, 33-37 Inhibit Aggregation of the Amyloidogenic Core of the Hormone. Chem Biodivers 2020; 18:e2000842. [PMID: 33331666 DOI: 10.1002/cbdv.202000842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 11/20/2020] [Indexed: 11/11/2022]
Abstract
Amylin (hIAPP) aggregation leads to the formation of insoluble deposits and is one of the factors in the development of type II diabetes. The aim of this research was to find N-methylated analogs of the aggregating amylin fragments 18-22, 23-27, and 33-37, which would not themselves be susceptible to aggregation and would inhibit the aggregation of the amyloidogenic cores of the hormone. None of the analogs of fragment 18-22 containing one or two N-methylated amino acid residues showed any tendency to aggregate. Only the peptide H-F(N-Me)GA(N-Me) IL-OH (6) derived from the 23-27 hIAPP hot spot did not form fibrous structures. All analogs of the 33-37 amylin fragment were characterized by the ability to form aggregates, despite the presence of N-methylated amino acids in their structures. N-Methylated peptides 1-5 demonstrated inhibitory properties against the aggregation of fragment 18-22. Aggregation of the amyloidogenic core of 23-27 was significantly inhibited by N-methylated peptides 1-3 derived from the (18-22) H-HSSNN-OH fragment and by the H-F(N-Me)GA(N-Me)IL-OH (6) fragment derived from the 23-27 amylin hot spot. Fragment (33-37) H-GSNTY-NH2 was found to be inhibited in the presence of N-methylated peptides 1-3 derived from the 18-22 fragment and by the double methylated peptide H-F(N-Me)GA(N-Me)IL-OH (6). Research on the possibility of using N-methylated analogs of amyloidogenic amylin cores as inhibitors of hormone aggregation is ongoing, with a focus on finding the minimum concentration of N-methylated peptides capable of inhibiting the aggregation of hIAPP hot spots.
Collapse
Affiliation(s)
- Kamil Rozniakowski
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland
| | - Krystian Galecki
- Institute of General Food Chemistry, Faculty of Biotechnology & Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924, Lodz, Poland
| | - Joanna Wietrzyk
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla St., 53-114, Wroclaw, Poland
| | - Beata Filip-Psurska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla St., 53-114, Wroclaw, Poland
| | - Justyna Fraczyk
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland
| | - Zbigniew J Kaminski
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland
| | - Beata Kolesinska
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland
| |
Collapse
|
|
30
|
Bloch DN, Ben Zichri S, Kolusheva S, Jelinek R. Tyrosine carbon dots inhibit fibrillation and toxicity of the human islet amyloid polypeptide. NANOSCALE ADVANCES 2020; 2:5866-5873. [PMID: 36133854 PMCID: PMC9419576 DOI: 10.1039/d0na00870b] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 11/09/2020] [Indexed: 05/04/2023]
Abstract
Misfolding and aggregation of the human islet amyloid polypeptide (hIAPP) are believed to play key roles in the pathophysiology of type-II diabetes. Here, we demonstrate that carbon dots (C-dots) prepared from the amino acid tyrosine inhibit fibrillation of hIAPP, reduce hIAPP-induced cell toxicity and block membrane disruption by the peptide. The pronounced inhibitory effect is traced to the display of ubiquitous aromatic residues upon the C-dots' surface, mimicking the anti-fibril and anti-toxic activity of natural polyphenolic compounds. Notably, spectroscopy and thermodynamics analysis demonstrated different hIAPP interactions and fibril inhibition effects induced by tyrosine-C-dots displaying phenolic residues and C-dots prepared from phenylalanine which exhibited phenyl units on their surface, underscoring the significance of hydrogen bonding mediated by the phenolic hydroxide moieties for the fibril modulation activity. The presented experiments attest to the potential of tyrosine-C-dots as a therapeutic vehicle for protein misfolding diseases, interfering in both π-π interactions as well as hydrogen bonding involving aromatic residues of amyloidogenic peptides.
Collapse
Affiliation(s)
- Daniel Nir Bloch
- Department of Chemistry, Ben Gurion University of the Negev Beer Sheva 84105 Israel
| | - Shani Ben Zichri
- Department of Chemistry, Ben Gurion University of the Negev Beer Sheva 84105 Israel
| | - Sofiya Kolusheva
- Ilse Katz Institute for Nano-Science and Technology (IKI), Ben Gurion University of the Negev Beer Sheva 84105 Israel
| | - Raz Jelinek
- Department of Chemistry, Ben Gurion University of the Negev Beer Sheva 84105 Israel
- Ilse Katz Institute for Nano-Science and Technology (IKI), Ben Gurion University of the Negev Beer Sheva 84105 Israel
| |
Collapse
|
|
31
|
Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity. Molecules 2020; 25:molecules25235698. [PMID: 33287192 PMCID: PMC7730986 DOI: 10.3390/molecules25235698] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/05/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023] Open
Abstract
One of the molecular hallmarks of amyloidoses is ordered protein aggregation involving the initial formation of soluble protein oligomers that eventually grow into insoluble fibrils. The identification and characterization of molecular species critical for amyloid fibril formation and disease development have been the focus of intense analysis in the literature. Here, using photo-induced cross-linking of unmodified proteins (PICUP), we studied the early stages of oligomerization of human transthyretin (TTR), a plasma protein involved in amyloid diseases (ATTR amyloidosis) with multiple clinical manifestations. Upon comparison, the oligomerization processes of wild-type TTR (TTRwt) and several TTR variants (TTRV30M, TTRL55P, and TTRT119M) clearly show distinct oligomerization kinetics for the amyloidogenic variants but a similar oligomerization mechanism. The oligomerization kinetics of the TTR amyloidogenic variants under analysis showed a good correlation with their amyloidogenic potential, with the most amyloidogenic variants aggregating faster (TTRL55P > TTRV30M > TTRwt). Moreover, the early stage oligomerization mechanism for these variants involves stepwise addition of monomeric units to the growing oligomer. A completely different behavior was observed for the nonamyloidogenic TTRT119M variant, which does not form oligomers in the same acidic conditions and even for longer incubation times. Thorough characterization of the initial steps of TTR oligomerization is critical for better understanding the origin of ATTR cytotoxicity and developing novel therapeutic strategies for the treatment of ATTR amyloidosis.
Collapse
|
|
32
|
Saghir AE, Farrugia G, Vassallo N. The human islet amyloid polypeptide in protein misfolding disorders: Mechanisms of aggregation and interaction with biomembranes. Chem Phys Lipids 2020; 234:105010. [PMID: 33227292 DOI: 10.1016/j.chemphyslip.2020.105010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/06/2020] [Accepted: 11/09/2020] [Indexed: 02/09/2023]
Abstract
Human islet amyloid polypeptide (hIAPP), otherwise known as amylin, is a 37-residue peptide hormone which is reported to be a common factor in protein misfolding disorders such as type-2 diabetes mellitus, Alzheimer's disease and Parkinson's disease, due to deposition of insoluble hIAPP amyloid in the pancreas and brain. Multiple studies point to the importance of the peptide's interaction with biological membranes and the cytotoxicity of hIAPP species. Here, we discuss the aggregation pathways of hIAPP amyloid fibril formation and focus on the complex interplay between membrane-mediated assembly of hIAPP and the associated mechanisms of membrane damage caused by the peptide species. Mitochondrial membranes, which are unique in their lipid composition, are proposed as prime targets for the early intracellular formation of hIAPP toxic entities. We suggest that future studies should include more physiologically-relevant and in-cell studies to allow a more accurate model of in vivo interactions. Finally, we underscore an urgent need for developing effective therapeutic strategies aimed at hindering hIAPP-phospholipid interactions.
Collapse
Affiliation(s)
- Adam El Saghir
- Dept. of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Gianluca Farrugia
- Dept. of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Neville Vassallo
- Dept. of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta.
| |
Collapse
|
|
33
|
Araújo AR, Reis RL, Pires RA. Natural Polyphenols as Modulators of the Fibrillization of Islet Amyloid Polypeptide. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1250:159-176. [PMID: 32601944 DOI: 10.1007/978-981-15-3262-7_11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Diabetes mellitus type 2 (type-2 diabetes) is a metabolic disorder characterized by the increased blood glucose concentration and insulin resistance in peripheral tissues (e.g., muscles and adipose tissue). The initiation of the pathological cascade of events that lead to type-2 diabetes has been subject of debate; however, it has been commonly accepted that the oversecretion of human islet amyloid polypeptide (hIAPP, a hormone co-secreted with insulin) by the pancreatic 𝛽-cells is the main trigger of type-2 diabetes. In fact, 90% of the type-2 diabetes patients present hIAPP deposits in the extracellular space of the 𝛽-cells. These hIAPP supramolecular arrangements (both fibrillar and oligomeric) have been reported to be the origin of cytotoxicity, which leads to 𝛽-cell dysfunction through a series of different mechanisms, including the interaction of hIAPP oligomers with the cell membrane that leads to the influx of Ca2+ and increase in the cellular oxidative stress, among others. This overview shows the importance of developing type-2 diabetes treatment strategies able to (1) remodel of the secondary structure of cytotoxic hIAPP oligomers entrapping them into off-pathway nontoxic species and (2) reestablish physiological levels of oxidative stress. Natural polyphenols are a class of antioxidant compounds that are able to perform both functions. Herein we review the published literature of the most studied polyphenols, in particular for their ability to remodel the hIAPP aggregation pathway, to rescue the in vitro pancreatic 𝛽-cell viability and function, as well as to perform under a complex biological environment, i.e., in vivo animal models and clinical trials. Overall, natural polyphenols are able to control the cytotoxic hIAPP aggregation and minimize hIAPP-mediated cellular dysfunction and can be considered as important lead compounds for the treatment of type-2 diabetes.
Collapse
Affiliation(s)
- Ana R Araújo
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
| | - Rui L Reis
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
| | - Ricardo A Pires
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, Guimarães, Portugal. .,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal. .,The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal.
| |
Collapse
|
|
34
|
Liu Y, Zhang D, Zhang Y, Tang Y, Xu L, He H, Wu J, Zheng J. Molecular Dynamics Simulations of Cholesterol Effects on the Interaction of hIAPP with Lipid Bilayer. J Phys Chem B 2020; 124:7830-7841. [DOI: 10.1021/acs.jpcb.0c05742] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Yonglan Liu
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio 44325, United States
| | - Dong Zhang
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio 44325, United States
| | - Yanxian Zhang
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio 44325, United States
| | - Yijing Tang
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio 44325, United States
| | - Lijian Xu
- Hunan Key Laboratory of Biomedical Nanomaterials and Devices College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, P. R. China
| | - Huacheng He
- College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325027, P. R. China
| | - Jiang Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P. R. China
| | - Jie Zheng
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio 44325, United States
| |
Collapse
|
|
35
|
Ke PC, Zhou R, Serpell LC, Riek R, Knowles TPJ, Lashuel HA, Gazit E, Hamley IW, Davis TP, Fändrich M, Otzen DE, Chapman MR, Dobson CM, Eisenberg DS, Mezzenga R. Half a century of amyloids: past, present and future. Chem Soc Rev 2020; 49:5473-5509. [PMID: 32632432 PMCID: PMC7445747 DOI: 10.1039/c9cs00199a] [Citation(s) in RCA: 355] [Impact Index Per Article: 71.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-β architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward.
Collapse
Affiliation(s)
- Pu Chun Ke
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
- Zhongshan Hospital, Fudan University, 111 Yixueyuan Rd, Xuhui District, Shanghai, China
| | - Ruhong Zhou
- Institute of Quantitative Biology, Zhejiang University, Hangzhou 310058, China; Department of Chemistry, Columbia University, New York, New York, 10027, USA
| | - Louise C. Serpell
- School of Life Sciences, University of Sussex, Falmer, East Sussex BN1 9QG, UK
| | - Roland Riek
- Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland
| | - Tuomas P. J. Knowles
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
- Cavendish Laboratory, University of Cambridge, J J Thomson Avenue, CB3 0HE, Cambridge, UK
| | - Hilal A. Lashuel
- Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Ehud Gazit
- Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences; Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, 69978 Tel Aviv, Israel
| | - Ian W. Hamley
- School of Chemistry, Food Biosciences and Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK
| | - Thomas P. Davis
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane Qld 4072, Australia
| | - Marcus Fändrich
- Institute of Protein Biochemistry, Ulm University, 89081, Ulm, Germany
| | - Daniel Erik Otzen
- Department of Molecular Biology, Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
| | - Matthew R. Chapman
- Department of Molecular, Cellular and Developmental Biology, Centre for Microbial Research, University of Michigan, Ann Arbor, MI 48109-1048, USA
| | - Christopher M. Dobson
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - David S. Eisenberg
- Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute and Howard Hughes Medical Institute, UCLA, Los Angeles, CA, USA
| | - Raffaele Mezzenga
- Department of Health Science & Technology, ETH Zurich, Schmelzbergstrasse 9, LFO, E23, 8092 Zurich, Switzerland
- Department of Materials, ETH Zurich, Wolfgang Pauli Strasse 10, 8093 Zurich, Switzerland
| |
Collapse
|
|
36
|
Pandey P, Nguyen N, Hansmann UHE. d-Retro Inverso Amylin and the Stability of Amylin Fibrils. J Chem Theory Comput 2020; 16:5358-5368. [PMID: 32667784 DOI: 10.1021/acs.jctc.0c00523] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Motivated by the role that amylin aggregates play in type-II diabetes, we compare the stability of regular amylin fibrils with the stability of fibrils where l-amino acid chains are replaced by d-retro inverso (DRI) amylin, that is, peptides where the sequence of amino acids is reversed, and at the same time, the l-amino acids are replaced by their mirror images. Our molecular dynamics simulations show that despite leading to only a marginal difference in the fibril structure and stability, aggregating DRI-amylin peptides have different patterns of contacts and hydrogen bonding. Because of these differences, DRI-amylin, when interacting with regular (l) amylin, alters the elongation process and lowers the stability of hybrid amylin fibrils. Our results not only suggest the potential use of DRI-amylin as an inhibitor of amylin fibril formation but also point to the possibility of using the insertion of DRI proteins in l-assemblies as a way to probe the role of certain kinds of hydrogen bonds in supramolecular assemblies or aggregates.
Collapse
Affiliation(s)
- Preeti Pandey
- Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Natalie Nguyen
- Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Ulrich H E Hansmann
- Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| |
Collapse
|
|
37
|
Abstract
The role of alpha-synuclein (αS) amyloid fibrillation has been recognized in various neurological diseases including Parkinson's Disease (PD). In early stages, fibrillation occurs by the structural transition from helix to extended states in monomeric αS followed by the formation of beta-sheets. This alpha-helix to beta-sheet transition (αβT) speeds up the formation of amyloid fibrils through the formation of unstable and temporary configurations of the αS. In this study, the most important regions that act as initiating nuclei and make unstable the initial configuration were identified based on sequence and structural information. In this regard, a Targeted Molecular Dynamics (TMD) simulation was employed using explicit solvent models under physiological conditions. Identified regions are those that are in the early steps of structural opening. The trajectory was clustered the structures characterized the intermediate states. The findings of this study would help us to better understanding of the mechanism of amyloid fibril formation.
Collapse
|
|
38
|
Disorder under stress: Role of polyol osmolytes in modulating fibrillation and aggregation of intrinsically disordered proteins. Biophys Chem 2020; 264:106422. [PMID: 32707418 DOI: 10.1016/j.bpc.2020.106422] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 12/18/2022]
Abstract
Intrinsically disordered proteins (IDPs) comprise ~30-40% of the proteome, have key roles in cellular processes, and have been reported to be involved in stress regulation working in synergy with osmolytes. Osmolytes are known to accumulate against various stresses in living systems and are known to stabilize the native conformation of globular proteins. However, little is known of their effect on IDPs and their mechanism of action is unclear. We have investigated the effect of a series of polyol osmolytes on the conformation, aggregation and fibrillation properties of the IDPs α and β-synuclein, involved in Parkinson's disease, using fluorescence, CD, light scattering and TEM. We observe inhibition of fibril and aggregate formation with increasing concentration as well as the number of hydroxyl groups in polyols as observed by light scattering measurements which correlates well with the increase in viscosity of solution with increasing number of OH groups in them. However, ThT assay, while indicating suppression of fibril formation at various concentrations of polyols, shows enhanced fibrillation at some other concentrations which could be due to the heterogeneity of the species formed that are ThT insensitive. Fibril formation was, thus, probed by using Nile red fluorescence which showed sensitivity towards the species formed. ANS binding fluorescence also indicates a decrease in the hydrophobicity of the fibrils with increasing number of OH groups in polyols. Polyols do not have any effect on the fibrillation of β-syn but lead to enhanced amorphous aggregate formation in presence of Ethylene Glycol and Glycerol and a reduction in the presence of Sorbitol. The net free energy of transfer of the proteins from water to Sorbitol is large and positive while it is relatively negligible in the case of Glycerol suggestive of greater preferential exclusion effect of Sorbitol in comparison with Glycerol in the case of IDPs as well. The results overall show differential and complex effect of osmolytes towards the fibrillation/aggregation properties of the two IDPs and suggest that an appropriate balance between the concentration and type of polyol or osmolyte would be required for the survival of organisms rich in IDPs under various stress conditions.
Collapse
|
|
39
|
Structural analyses and force fields comparison for NACore (68-78) and SubNACore (69-77) fibril segments of Parkinson's disease. J Mol Model 2020; 26:132. [PMID: 32394304 DOI: 10.1007/s00894-020-04379-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 04/07/2020] [Indexed: 10/24/2022]
Abstract
The α-synuclein fibrils are a pathological hallmark of Parkinson's disease (PD) and are abundant in the brains of PD patients. These amyloid fibrils can aggregate into distinct polymorphism under different physical conditions. Therefore, these different fibril polymorph formations should be considered in drug design studies targeting amyloid fibrils. Recently, the atomic structures of two small fibril segments of α-synuclein, named NACore (68-78) and SubNACore (69-77), have been crystallized. These segments are critical for cytotoxicity and fibril formation. Therefore, elucidation of interface interactions between pair sheets of the NACore and SubNACore is significant for the clarification of the mechanism of fibril formation in PD. In this context, molecular dynamics (MD) simulation technique is a convenient tool to investigate interface interactions of these segments at the atomic level. However, the accuracy of these simulations depends on the utilized force fields. Therefore, we have tested the dependence of interface interactions and stabilities of these small amyloid fibrils on various force fields. From the results of triple long (100 ns) MD simulations, we inferred for the stability investigations of the NACore and SubNACore that CHARMM27 and GROMOS53A6 are the most convenient force fields whereas AMBER99SB-ILDN is the most unfavorable one. Consequently, it is expected that our findings will guide the selection of the appropriate force field for simulations between these segments and possible inhibitors of this disease.
Collapse
|
|
40
|
Abstract
Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.
Collapse
|
|
41
|
Xuan Q, He J, Li M, Chai R, Wang C, Wang Y, Wang P. Monomer-targeting affinity peptide inhibitors of amyloid with no self-fibrillation and low cytotoxicity. Chem Commun (Camb) 2020; 56:1633-1636. [DOI: 10.1039/c9cc08671d] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A monomer-targeting strategy based on solution-phase biopanning to obtain peptide inhibitors increases the suppression efficiency and reduces the cytotoxicity of amylin.
Collapse
Affiliation(s)
- Qize Xuan
- State Key Laboratory of Bioreactor Engineering
- Biomedical Nanotechnology Center
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology
- School of Biotechnology
- East China University of Science and Technology
| | - Jiaxin He
- State Key Laboratory of Bioreactor Engineering
- Biomedical Nanotechnology Center
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology
- School of Biotechnology
- East China University of Science and Technology
| | - Min Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety
- Institute of High Energy Physics
- Chinese Academy of Sciences
- Beijing 100049
- China
| | - Ruoshi Chai
- State Key Laboratory of Bioreactor Engineering
- Biomedical Nanotechnology Center
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology
- School of Biotechnology
- East China University of Science and Technology
| | - Chenxuan Wang
- State Key Laboratory of Medical Molecular Biology
- Institute of Basic Medical Sciences
- Chinese Academy of Medical Sciences
- Department of Biophysics and Structural Biology
- Peking Union Medical College
| | - Yibing Wang
- State Key Laboratory of Bioreactor Engineering
- Biomedical Nanotechnology Center
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology
- School of Biotechnology
- East China University of Science and Technology
| | - Ping Wang
- Department of Bioproducts and Biosystems Engineering
- University of Minnesota
- St Paul
- USA
| |
Collapse
|
|
42
|
Salazar Vazquez S, Blondeau B, Cattan P, Armanet M, Guillemain G, Khemtemourian L. The flanking peptides issue from the maturation of the human islet amyloid polypeptide (hIAPP) slightly modulate hIAPP-fibril formation but not hIAPP-induced cell death. Biochimie 2019; 170:26-35. [PMID: 31838129 DOI: 10.1016/j.biochi.2019.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 12/10/2019] [Indexed: 01/13/2023]
Abstract
Type 2 diabetes mellitus is a disease characterized by the formation of amyloid fibrillar deposits consisting mainly in human islet amyloid polypeptide (hIAPP), a peptide co-produced and co-secreted with insulin. hIAPP and insulin are synthesized by pancreatic β cells initially as prehormones resulting after sequential cleavages in the mature peptides as well as the two flanking peptides (N- and C-terminal) and the C-peptide, respectively. It has been suggested that in the secretory granules, the kinetics of hIAPP fibril formation could be modulated by some internal factors. Indeed, insulin is known to be a potent inhibitor of hIAPP fibril formation and hIAPP-induced cell toxicity. Here we investigate whether the flanking peptides could regulate hIAPP fibril formation and toxicity by combining biophysical and biological approaches. Our data reveal that both flanking peptides are not amyloidogenic. In solution and in the presence of phospholipid membranes, they are not able to totally inhibit hIAPP-fibril formation neither hIAPP-membrane damage. In the presence of INS-1 cells, a rat pancreatic β-cell line, the flanking peptides do not modulate hIAPP fibrillation neither hIAPP-induced cell death while in the presence of human islets, they have a slightly tendency to reduce hIAPP fibril formation but not its toxicity. These data demonstrate that the flanking peptides do not strongly contribute to reduce mature hIAPP amyloidogenesis in solution and in living cells, suggesting that other biochemical factors present in the cells must act on mature hIAPP fibril formation and hIAPP-induced cell death.
Collapse
Affiliation(s)
- Shadai Salazar Vazquez
- Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM), 4 Place Jussieu, F-75005, Paris, France
| | - Bertrand Blondeau
- Sorbonne Université, Inserm UMR_S938, Centre de Recherche de St-Antoine, Lipodystrophies, Adaptations Métaboliques et Hormonales, et Vieillissement, 27 Rue de Chaligny, 75012, Paris, France
| | - Pierre Cattan
- Cell Therapy Unit, Hospital Saint-Louis and University Paris-Diderot, Paris, France
| | - Mathieu Armanet
- Cell Therapy Unit, Hospital Saint-Louis and University Paris-Diderot, Paris, France
| | - Ghislaine Guillemain
- Sorbonne Université, Inserm UMR_S938, Centre de Recherche de St-Antoine, Lipodystrophies, Adaptations Métaboliques et Hormonales, et Vieillissement, 27 Rue de Chaligny, 75012, Paris, France.
| | - Lucie Khemtemourian
- Sorbonne Université, Ecole Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM), 4 Place Jussieu, F-75005, Paris, France.
| |
Collapse
|
|
43
|
Jokar S, Khazaei S, Behnammanesh H, Shamloo A, Erfani M, Beiki D, Bavi O. Recent advances in the design and applications of amyloid-β peptide aggregation inhibitors for Alzheimer's disease therapy. Biophys Rev 2019; 11:10.1007/s12551-019-00606-2. [PMID: 31713720 DOI: 10.1007/s12551-019-00606-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 10/31/2019] [Indexed: 01/05/2023] Open
Abstract
Alzheimer's disease (AD) is an irreversible neurological disorder that progresses gradually and can cause severe cognitive and behavioral impairments. This disease is currently considered a social and economic incurable issue due to its complicated and multifactorial characteristics. Despite decades of extensive research, we still lack definitive AD diagnostic and effective therapeutic tools. Consequently, one of the most challenging subjects in modern medicine is the need for the development of new strategies for the treatment of AD. A large body of evidence indicates that amyloid-β (Aβ) peptide fibrillation plays a key role in the onset and progression of AD. Recent studies have reported that amyloid hypothesis-based treatments can be developed as a new approach to overcome the limitations and challenges associated with conventional AD therapeutics. In this review, we will provide a comprehensive view of the challenges in AD therapy and pathophysiology. We also discuss currently known compounds that can inhibit amyloid-β (Aβ) aggregation and their potential role in advancing current AD treatments. We have specifically focused on Aβ aggregation inhibitors including metal chelators, nanostructures, organic molecules, peptides (or peptide mimics), and antibodies. To date, these molecules have been the subject of numerous in vitro and in vivo assays as well as molecular dynamics simulations to explore their mechanism of action and the fundamental structural groups involved in Aβ aggregation. Ultimately, the aim of these studies (and current review) is to achieve a rational design for effective therapeutic agents for AD treatment and diagnostics.
Collapse
Affiliation(s)
- Safura Jokar
- Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. BOX: 14155-6559, Tehran, Iran
| | - Saeedeh Khazaei
- Department of Pharmaceutical Biomaterials , Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. BOX: 14155-6559, Tehran, Iran
| | - Hossein Behnammanesh
- Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. BOX: 14155-6559, Tehran, Iran
| | - Amir Shamloo
- Department of Mechanical Engineering, Sharif University of Technology, P.O. Box: 11365-11155, Tehran, Iran
| | - Mostafa Erfani
- Radiation Application Research School, Nuclear Science and Technology Research Institute (NSTRI), P.O. Box: 14155-1339, Tehran, Iran
| | - Davood Beiki
- Research Center for Nuclear Medicine, Tehran University of Medical Sciences, P.O. BOX: 14155-6559, Tehran, Iran
| | - Omid Bavi
- Department of Mechanical and Aerospace Engineering, Shiraz University of Technology, P.O. Box: 71555-313, Shiraz, Iran.
| |
Collapse
|
|
44
|
Martinez-Valbuena I, Valenti-Azcarate R, Amat-Villegas I, Riverol M, Marcilla I, de Andrea CE, Sánchez-Arias JA, Del Mar Carmona-Abellan M, Marti G, Erro ME, Martínez-Vila E, Tuñon MT, Luquin MR. Amylin as a potential link between type 2 diabetes and alzheimer disease. Ann Neurol 2019; 86:539-551. [PMID: 31376172 DOI: 10.1002/ana.25570] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and β-amyloid (Aβ) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. METHODS We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined Aβ and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or Aβ interact with amylin in either the pancreas or brain of these subjects. RESULTS Cytoplasmic tau and Aβ protein deposits were detected in pancreatic β cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with Aβ and tau in both the pancreas and hippocampus. INTERPRETATION The presence of both tau and Aβ inclusions in pancreatic β cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019;86:539-551.
Collapse
Affiliation(s)
- Ivan Martinez-Valbuena
- Neurology Department, Clínica Universidad de Navarra, Pamplona, Spain
- Regenerative Therapy Laboratory, Neurosciences Division, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Navarra Health Research Institute, Pamplona, Spain
| | - Rafael Valenti-Azcarate
- Neurology Department, Clínica Universidad de Navarra, Pamplona, Spain
- Regenerative Therapy Laboratory, Neurosciences Division, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Navarra Health Research Institute, Pamplona, Spain
| | - Irene Amat-Villegas
- Navarra Health Research Institute, Pamplona, Spain
- Pathology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Mario Riverol
- Neurology Department, Clínica Universidad de Navarra, Pamplona, Spain
- Navarra Health Research Institute, Pamplona, Spain
| | - Irene Marcilla
- Regenerative Therapy Laboratory, Neurosciences Division, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Navarra Health Research Institute, Pamplona, Spain
| | | | - Juan Antonio Sánchez-Arias
- Navarra Health Research Institute, Pamplona, Spain
- Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Maria Del Mar Carmona-Abellan
- Neurology Department, Clínica Universidad de Navarra, Pamplona, Spain
- Regenerative Therapy Laboratory, Neurosciences Division, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Navarra Health Research Institute, Pamplona, Spain
| | - Gloria Marti
- Neurology Department, Clínica Universidad de Navarra, Pamplona, Spain
- Navarra Health Research Institute, Pamplona, Spain
| | - Maria-Elena Erro
- Navarra Health Research Institute, Pamplona, Spain
- Neurology Department, Navarra Hospital Complex, Pamplona, Spain
| | - Eduardo Martínez-Vila
- Neurology Department, Clínica Universidad de Navarra, Pamplona, Spain
- Navarra Health Research Institute, Pamplona, Spain
| | - Maria-Teresa Tuñon
- Navarra Health Research Institute, Pamplona, Spain
- Pathology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Maria-Rosario Luquin
- Neurology Department, Clínica Universidad de Navarra, Pamplona, Spain
- Regenerative Therapy Laboratory, Neurosciences Division, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Navarra Health Research Institute, Pamplona, Spain
| |
Collapse
|
|
45
|
Grizzanti J, Corrigan R, Casadesus G. Neuroprotective Effects of Amylin Analogues on Alzheimer's Disease Pathogenesis and Cognition. J Alzheimers Dis 2019; 66:11-23. [PMID: 30282360 DOI: 10.3233/jad-180433] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer's disease (AD). Interestingly, both AD and T2D have similar characteristics including amyloid peptide aggregation, decreased metabolism, and increased oxidative stress and inflammation. Despite their prevalence, therapies for these diseases are limited. To date, most therapies for AD have targeted amyloid-β or tau. Unfortunately, most of these clinical trials have been largely unsuccessful, creating a crucial need for novel therapies. A number of studies have shown that metabolic hormone therapies are effective at ameliorating high blood glucose levels in diabetics as well as improving cognitive function in AD and mild cognitive impairment patients. Pramlintide, a synthetic analogue of the pancreatic hormone amylin, has been developed and used for years now as a treatment for both type I diabetes and T2D due to the loss of β-islet cells responsible for producing amylin. Importantly, recent data demonstrates its potential therapeutic role for AD as well. This review aims at addressing parallels between T2D and AD at a pathological and functional level, focusing on amylin signaling as a key, overlapping mediator in both diseases. The potential therapeutic use of this hormone to treat AD will also be explored from a mechanistic viewpoint.
Collapse
Affiliation(s)
- John Grizzanti
- School of Biomedical Sciences, Kent State University, Kent, OH, USA
| | - Rachel Corrigan
- School of Biomedical Sciences, Kent State University, Kent, OH, USA
| | - Gemma Casadesus
- School of Biomedical Sciences, Kent State University, Kent, OH, USA.,Department of Biological Sciences, Kent State University, Kent, OH, USA
| |
Collapse
|
|
46
|
Christensen M, Schiøtt B. Revealing a Dual Role of Ganglioside Lipids in the Aggregation of Membrane-Associated Islet Amyloid Polypeptide. J Membr Biol 2019; 252:343-356. [DOI: 10.1007/s00232-019-00074-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 06/09/2019] [Indexed: 12/31/2022]
|
|
47
|
Ilie IM, Caflisch A. Simulation Studies of Amyloidogenic Polypeptides and Their Aggregates. Chem Rev 2019; 119:6956-6993. [DOI: 10.1021/acs.chemrev.8b00731] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Ioana M. Ilie
- Department of Biochemistry, University of Zürich, Zürich CH-8057, Switzerland
| | - Amedeo Caflisch
- Department of Biochemistry, University of Zürich, Zürich CH-8057, Switzerland
| |
Collapse
|
|
48
|
Zhang XX, Qiao YC, Li W, Zou X, Chen YL, Shen J, Liao QY, Zhang QJ, He L, Zhao HL. Human amylin induces CD4+Foxp3+ regulatory T cells in the protection from autoimmune diabetes. Immunol Res 2019; 66:179-186. [PMID: 28983871 DOI: 10.1007/s12026-017-8956-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Autoimmune diabetes is a disorder of immune homeostasis that leads to targeted insulin-secreting islet β cell destruction characterized by insulitis. Human amylin (hA) is an important neuroendocrine hormone co-secreted with insulin by pancreatic β cells. Here, we report hA immune-modulatory action through inducing regulatory T cells. We ex vivo-treated human peripheral blood mononuclear cells (hPBMCs) with hA for 24 h and counted CD4+Foxp3+ regulatory T cells (Treg) using flow cytometry. Diabetic status was monitored and splenic Treg were measured in non-obese diabetic (NOD) male mice. NOD mice were intraperitoneally injected once daily with hA (n = 25) or solvent for control (n = 25) for 7 months continuously. Spleen tissues were collected at the end of intervention and processed for flow cytometry and Western blot. We found a 2.9-fold (p < 0.05) increase of CD4+Foxp3+ Treg in hPBMCs treated with 10 nmol/L hA compared with negative control. Incidence of diabetes in hA-treated NOD mice decreased 44% (p = 0.045) in the 6th month and 57% (p = 0.0002) in the 7th month. Meanwhile, the hA treatment induced a 1.5-fold increase of CD4+Foxp3+ Treg from mouse splenocytes (p = 0.0013). Expression of transforming growth factor-β (TGF-β) and toll-like receptor-4 (TLR-4) were upregulated in hA-treated mice. Human amylin might protect against autoimmune diabetes via the induction of CD4+Foxp3+ Treg, which suggests a novel approach to improve autoimmune conditions.
Collapse
Affiliation(s)
- Xiao-Xi Zhang
- Centre of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Huan Cheng North 2nd Road 109, Guilin, Guangxi, 541004, China
| | - Yong-Chao Qiao
- Department of Immunology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Wan Li
- Centre of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Huan Cheng North 2nd Road 109, Guilin, Guangxi, 541004, China
| | - Xia Zou
- Centre of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Huan Cheng North 2nd Road 109, Guilin, Guangxi, 541004, China
| | - Yin-Ling Chen
- Centre of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Huan Cheng North 2nd Road 109, Guilin, Guangxi, 541004, China
| | - Jian Shen
- Centre of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Huan Cheng North 2nd Road 109, Guilin, Guangxi, 541004, China
| | - Qin-Yuan Liao
- Centre of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Huan Cheng North 2nd Road 109, Guilin, Guangxi, 541004, China
| | - Qiu-Jin Zhang
- Centre of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Huan Cheng North 2nd Road 109, Guilin, Guangxi, 541004, China
| | - Lan He
- Department of Microbiology, Prince of Wales Hospital, Shatin, Hong Kong
| | - Hai-Lu Zhao
- Centre of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Immunology, Guangxi Area of Excellence, Guilin Medical University, Huan Cheng North 2nd Road 109, Guilin, Guangxi, 541004, China. .,Department of Immunology, Guilin Medical University, Guilin, Guangxi, 541004, China.
| |
Collapse
|
|
49
|
Vidal-Martinez G, Yang B, Vargas-Medrano J, Perez RG. Could α-Synuclein Modulation of Insulin and Dopamine Identify a Novel Link Between Parkinson's Disease and Diabetes as Well as Potential Therapies? Front Mol Neurosci 2018; 11:465. [PMID: 30622456 PMCID: PMC6308185 DOI: 10.3389/fnmol.2018.00465] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 11/30/2018] [Indexed: 12/12/2022] Open
Abstract
Characterizing the normal function(s) of the protein α-Synuclein (aSyn) has the potential to illuminate links between Parkinson’s disease (PD) and diabetes and also point the way toward new therapies for these disorders. Here we provide a perspective for consideration based on our discovery that aSyn normally acts to inhibit insulin secretion from pancreatic β-cells by interacting with the Kir6.2 subunit of the ATP-sensitive potassium channel (K-ATP). It is also known that K-ATP channels act to inhibit brain dopamine secretion, and we have also shown that aSyn is a normal inhibitor of dopamine synthesis. The finding, that aSyn modulates Kir6.2 and other proteins involved in dopamine and insulin secretion, suggests that aSyn interacting proteins may be negatively impacted when aSyn aggregates inside cells, whether in brain or pancreas. Furthermore, identifying therapies for PD that can counteract dysfunction found in diabetes, would be highly beneficial. One such compound may be the multiple sclerosis drug, FTY720, which like aSyn can stimulate the activity of the catalytic subunit of protein phosphatase 2A (PP2Ac) as well as insulin secretion. In aging aSyn transgenic mice given long term oral FTY720, the mice had reduced aSyn pathology and increased levels of the protective molecule, brain derived neurotrophic factor (BDNF) (Vidal-Martinez et al., 2016). In collaboration with medicinal chemists, we made two non-immunosuppressive FTY720s that also enhance PP2Ac activity, and BDNF expression (Vargas-Medrano et al., 2014; Enoru et al., 2016; Segura-Ulate et al., 2017a). FTY720 and our novel FTY720-based-derivatives, may thus have therapeutic potential for both diabetes and PD.
Collapse
Affiliation(s)
- Guadalupe Vidal-Martinez
- Department of Biomedical Sciences, Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Barbara Yang
- Department of Biomedical Sciences, Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Javier Vargas-Medrano
- Department of Biomedical Sciences, Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Ruth G Perez
- Department of Biomedical Sciences, Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| |
Collapse
|
|
50
|
Hoffmann AR, Saravanan MS, Lequin O, Killian JA, Khemtemourian L. A single mutation on the human amyloid polypeptide modulates fibril growth and affects the mechanism of amyloid-induced membrane damage. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2018; 1860:1783-1792. [DOI: 10.1016/j.bbamem.2018.02.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/19/2018] [Accepted: 02/20/2018] [Indexed: 12/30/2022]
|