scholarly journals Amyloids: Regulators of Metal Homeostasis in the Synapse

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1441 ◽  
Author(s):  
Masahiro Kawahara ◽  
Midori Kato-Negishi ◽  
Ken-ichiro Tanaka
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Critical Role ◽  
Lewy Body Disease ◽  
Metal Homeostasis ◽  
Amyloidogenic Proteins ◽  
Neurodegenerative Process ◽  
Amyloid Oligomers ◽  
Associated Proteins ◽  
Regulatory Functions

Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.

scholarly journals Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases

2010 ◽  
Vol 12 ◽  
Author(s):  
Jacques Fantini ◽  
Nouara Yahi
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Amyloid Fibrils ◽  
Fine Tuning ◽  
Neural Cells ◽  
Amyloidogenic Proteins ◽  
Innovative Therapies ◽  
Conformational Plasticity ◽  
Direct Binding ◽  
Α Helix

Alzheimer, Parkinson and other neurodegenerative diseases involve a series of brain proteins, referred to as ‘amyloidogenic proteins’, with exceptional conformational plasticity and a high propensity for self-aggregation. Although the mechanisms by which amyloidogenic proteins kill neural cells are not fully understood, a common feature is the concentration of unstructured amyloidogenic monomers on bidimensional membrane lattices. Membrane-bound monomers undergo a series of lipid-dependent conformational changes, leading to the formation of oligomers of varying toxicity rich in β-sheet structures (annular pores, amyloid fibrils) or in α-helix structures (transmembrane channels). Condensed membrane nano- or microdomains formed by sphingolipids and cholesterol are privileged sites for the binding and oligomerisation of amyloidogenic proteins. By controlling the balance between unstructured monomers and α or β conformers (the chaperone effect), sphingolipids can either inhibit or stimulate the oligomerisation of amyloidogenic proteins. Cholesterol has a dual role: regulation of protein–sphingolipid interactions through a fine tuning of sphingolipid conformation (indirect effect), and facilitation of pore (or channel) formation through direct binding to amyloidogenic proteins. Deciphering this complex network of molecular interactions in the context of age- and disease-related evolution of brain lipid expression will help understanding of how amyloidogenic proteins induce neural toxicity and will stimulate the development of innovative therapies for neurodegenerative diseases.

Amyloidogenic metal-binding proteins: new investigative pathways

2008 ◽  
Vol 36 (6) ◽  
pp. 1299-1303 ◽  
Author(s):  
Paul Davies ◽  
Sarah N. Fontaine ◽  
Dima Moualla ◽  
Xiaoyan Wang ◽  
Josephine A. Wright ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Metal Binding ◽  
Binding Proteins ◽  
Normal Function ◽  
Amyloidogenic Proteins ◽  
Logical Reason ◽  
Associated Proteins ◽  
Β Amyloid

Neurodegenerative diseases remain perplexing and problematic for modern research. Those associated with amyloidogenic proteins have often been lumped together simply because those proteins aggregate. However, research has identified a more logical reason to group some of these diseases together. The associated proteins not only aggregate, but also bind copper. The APP (amyloid precursor protein) binds copper in an N-terminal region. Binding of copper has been suggested to influence generation of β-amyloid from the protein. PrP (prion protein) binds copper, and this appears to be necessary for its normal function and might also reduce its probability of conversion into an infectious prion. α-Synuclein, a protein associated with Parkinson's disease, also binds copper, but, in this case, it potentially increases the rate at which the protein aggregates. The similarities between these proteins, in terms of metal binding, has allowed us to investigate them using similar approaches. In the present review, we discuss some of these approaches.

Crystal structures of Magnaporthe oryzae trehalose-6-phosphate synthase (MoTps1) suggest a model for catalytic process of Tps1

2019 ◽  
Vol 476 (21) ◽  
pp. 3227-3240 ◽  
Author(s):  
Shanshan Wang ◽  
Yanxiang Zhao ◽  
Long Yi ◽  
Minghe Shen ◽  
Chao Wang ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Magnaporthe Oryzae ◽  
Structural Information ◽  
Complex Structure ◽  
Critical Role ◽  
Catalytic Process ◽  
Structural Basis ◽  
Salt Bridges ◽  
Terminal Domain

Trehalose-6-phosphate (T6P) synthase (Tps1) catalyzes the formation of T6P from UDP-glucose (UDPG) (or GDPG, etc.) and glucose-6-phosphate (G6P), and structural basis of this process has not been well studied. MoTps1 (Magnaporthe oryzae Tps1) plays a critical role in carbon and nitrogen metabolism, but its structural information is unknown. Here we present the crystal structures of MoTps1 apo, binary (with UDPG) and ternary (with UDPG/G6P or UDP/T6P) complexes. MoTps1 consists of two modified Rossmann-fold domains and a catalytic center in-between. Unlike Escherichia coli OtsA (EcOtsA, the Tps1 of E. coli), MoTps1 exists as a mixture of monomer, dimer, and oligomer in solution. Inter-chain salt bridges, which are not fully conserved in EcOtsA, play primary roles in MoTps1 oligomerization. Binding of UDPG by MoTps1 C-terminal domain modifies the substrate pocket of MoTps1. In the MoTps1 ternary complex structure, UDP and T6P, the products of UDPG and G6P, are detected, and substantial conformational rearrangements of N-terminal domain, including structural reshuffling (β3–β4 loop to α0 helix) and movement of a ‘shift region' towards the catalytic centre, are observed. These conformational changes render MoTps1 to a ‘closed' state compared with its ‘open' state in apo or UDPG complex structures. By solving the EcOtsA apo structure, we confirmed that similar ligand binding induced conformational changes also exist in EcOtsA, although no structural reshuffling involved. Based on our research and previous studies, we present a model for the catalytic process of Tps1. Our research provides novel information on MoTps1, Tps1 family, and structure-based antifungal drug design.

Current Challenges and Limitations in the Studies of Intrinsically Disordered Proteins in Neurodegenerative Diseases by Computer Simulations

2020 ◽  
Vol 17 ◽  
Author(s):  
Ibrahim Yagiz Akbayrak ◽  
Sule Irem Caglayan ◽  
Zilan Ozcan ◽  
Vladimir N. Uversky ◽  
Orkid Coskuner-Weber
Keyword(s):  
Neurodegenerative Diseases ◽  
Computer Simulations ◽  
Conformational Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Computational Studies ◽  
Accurate Data ◽  
Aggregation Propensity ◽  
Intrinsically Disordered ◽  
Future Developments

: Experiments face challenges in the analysis of intrinsically disordered proteins in solution due to fast conformational changes and enhanced aggregation propensity. Computational studies complement experiments, being widely used in the analyses of intrinsically disordered proteins, especially those positioned at the centers of neurodegenerative diseases. However, recent investigations – including our own – revealed that computer simulations face significant challenges and limitations themselves. In this review, we introduced and discussed some of the scientific challenges and limitations of computational studies conducted on intrinsically disordered proteins. We also outlined the importance of future developments in the areas of computational chemistry and computational physics that would be needed for generating more accurate data for intrinsically disordered proteins from computer simulations. Additional theoretical strategies that can be developed are discussed herein.

scholarly journals HIV-1 Envelope Conformation, Allostery, and Dynamics

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 852
Author(s):  
Ashley Lauren Bennett ◽  
Rory Henderson
Keyword(s):  
Host Cell ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Cell Receptor ◽  
Broadly Neutralizing Antibodies ◽  
Structural Mapping ◽  
Host Cell Receptor ◽  
Immunogen Design ◽  
Hiv 1

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

Diffusible amyloid oligomers trigger systemic amyloidosis in mice

2008 ◽  
Vol 415 (2) ◽  
pp. 207-215 ◽  
Author(s):  
Sivanesan Senthilkumar ◽  
Edwin Chang ◽  
Rajadas Jayakumar
Keyword(s):  
Protein A ◽  
Mouse Tissue ◽  
Cytokine Induction ◽  
Amyloidogenic Proteins ◽  
Enhancing Factor ◽  
Amyloid Oligomers ◽  
Apparent Relationship ◽  
Amyloid Enhancing Factor ◽  
Local Accumulation

AA (amyloid protein A) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an intravenous injection of protein extracted from AA-laden mouse tissue. Previous findings affirm that AA fibrils can enhance the in vivo amyloidogenic process by a nucleation seeding mechanism. Accumulating evidence suggests that globular aggregates rather than fibrils are the toxic entities responsible for cell death. In the present study we report on structural and morphological features of AEF (amyloid-enhancing factor), a compound extracted and partially purified from amyloid-laden spleen. Surprisingly, the chief amyloidogenic material identified in the active AEF was diffusible globular oligomers. This partially purified active extract triggered amyloid deposition in vital organs when injected intravenously into mice. This implies that such a phenomenon could have been inflicted through the nucleation seeding potential of toxic oligomers in association with altered cytokine induction. In the present study we report an apparent relationship between altered cytokine expression and AA accumulation in systemically inflamed tissues. The prevalence of serum AA monomers and proteolytic oligomers in spleen AEF is consistent to suggest that extrahepatic serum AA processing might lead to local accumulation of amyloidogenic proteins at the serum AA production site.

scholarly journals The Annexin A2/S100A10 System in Health and Disease: Emerging Paradigms

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Nadia Hedhli ◽  
Domenick J. Falcone ◽  
Bihui Huang ◽  
Gabriela Cesarman-Maus ◽  
Rosemary Kraemer ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Human Cancer ◽  
High Titer ◽  
Critical Role ◽  
Annexin A2 ◽  
Avascular Osteonecrosis ◽  
Kinase Substrate ◽  
New Findings ◽  
Human Disorders ◽  
Associated Proteins

Since its discovery as a src kinase substrate more than three decades ago, appreciation for the physiologic functions of annexin A2 and its associated proteins has increased dramatically. With its binding partner S100A10 (p11), A2 forms a cell surface complex that regulates generation of the primary fibrinolytic protease, plasmin, and is dynamically regulated in settings of hemostasis and thrombosis. In addition, the complex is transcriptionally upregulated in hypoxia and promotes pathologic neoangiogenesis in the tissues such as the retina. Dysregulation of both A2 and p11 has been reported in examples of rodent and human cancer. Intracellularly, A2 plays a critical role in endosomal repair in postarthroplastic osteolysis, and intracellular p11 regulates serotonin receptor activity in psychiatric mood disorders. In human studies, the A2 system contributes to the coagulopathy of acute promyelocytic leukemia, and is a target of high-titer autoantibodies in patients with antiphospholipid syndrome, cerebral thrombosis, and possibly preeclampsia. Polymorphisms in the humanANXA2gene have been associated with stroke and avascular osteonecrosis of bone, two severe complications of sickle cell disease. Together, these new findings suggest that manipulation of the annexin A2/S100A10 system may offer promising new avenues for treatment of a spectrum of human disorders.

Abstract 260: Autophagy And Necrosis Underlie Polyglutamine Amyloid Oligomer Induced Heart Failure.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Scott Pattison ◽  
Atsushi Sanbe ◽  
Raisa Klevitsky ◽  
Hanna Osinska ◽  
Jeffrey Robbins
Keyword(s):  
Heart Failure ◽  
Neurodegenerative Diseases ◽  
Pathogenic Mechanism ◽  
Positive Staining ◽  
Neural Cells ◽  
Conformational Structure ◽  
Human Heart Failure ◽  
Specific Expression ◽  
Amyloid Oligomers ◽  
Amyloid Oligomer

Introduction: Amyloid oligomers, the entities believed to cause toxicity in many neurodegenerative diseases, have been observed in mouse and human heart failure samples. Amyloid oligomers are a diverse group of proteins that differ in sequence, but share a common conformational structure, and may impart a shared pathogenic mechanism. The purpose of this study was to test the hypothesis that expression and accumulation of amyloid oligomers are cytotoxic and sufficient to directly cause heart failure. Polyglutamine (PQ) repeats (>50) are known to form amyloid oligomers and induce toxicity in neural cells, causing Huntington′s and other neurodegenerative diseases, while shorter PQ peptides are benign. Hypothesis: Cardiomyocyte-autonomous expression of an exogenous PQ amyloid oligomer will be toxic to cardiomyocytes and result in heart failure. Methods: Transgenic mice were created with cardiomyocyte-specific expression of an amyloid oligomer forming peptide of 83 PQ repeats (PQ83) or a non-amyloid forming peptide of 19 PQ repeats (PQ19) as a non-pathological control. Both constructs were HA tagged. Results: A PQ83 line with relatively low levels of expression was generated, along with a PQ19 line that expressed at approximately 9-fold the levels observed in the PQ83 line. Hearts expressing PQ83 develop cardiac dysfunction and dilation by 5 months and exhibit 100% mortality by 8 months of age, whereas PQ19 mice have normal cardiac function, morphology and lifespan. PQ83 protein accumulates in cardiomyocytes as SDS-insoluble aggresomes with amyloid oligomer-positive staining. PQ83 hearts exhibited no signs of apoptosis. Ultrastructural analysis revealed that PQ83 hearts undergo autophagy, as evidenced by increased autophagosomal and lysosomal content. PQ83 hearts also show characteristics of necrotic death, including infiltration of inflammatory cells, cardiomyocyte vacuolization and increased staining for the membrane attack complex that causes sarcolemmal permeabilization. The data confirm the hypothesis that expression of an exogenous amyloid oligomer is toxic to cardiomyocytes and is sufficient to cause heart failure. The pathogenic mechanism appears to lead to cardiomyocyte death through autophagy and necrosis.

scholarly journals The disorder of the iron metabolism as a possible mechanism for the development of neurodegeneration after new coronavirus infection of SARS-CoV-2

2021 ◽  
Vol 40 (4) ◽  
pp. 13-24
Author(s):  
Igor V. Litvinenko ◽  
Igor V. Krasakov
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Brain Structures ◽  
Pathological Process ◽  
Parkinsons Disease ◽  
Neurodegenerative Process ◽  
Coronavirus Infection

The involvement of the nervous system in the pathological process that occurs when COVID-19 is infected is becoming more and more obvious. The question of the possibility of the debut or progression of the already developed Parkinsonism syndrome in patients who have undergone COVID-19 is regularly raised. A large number of hypotheses are put forward to explain this relationship. It is assumed that a violation of iron metabolism in the brain may underlie the development and progression of neurodegenerative diseases, including after the new coronavirus infection SARS-CoV-2. The analysis of stu dies on the possible influence of iron metabolism disorders on the occurrence and mechanism of development of neurodegenerative diseases after infection with SARS-CoV-2 has been carried out. The processes of physiological maintenance of iron homeostasis, as well as the influence of physiological aging on the accumulation of iron in the central nervous system are described. The relationship between hyperferritinemia occurring in COVID-19 and ferroptosis as the basis of the neurodegenerative process in Parkinsons disease and Alzheimers disease is discussed. The main molecular mechanisms involved in ferroptosis are described. Examples of involvement of metal homeostasis disorders in the process of altering the structure of -synuclein, synthesis of -amyloid, hyperphosphorylated tau- protein are given. The causes of excessive iron accumulation in certain brain structures are discussed. The question of the possibility of using the assessment of changes in iron metabolism as a new biomarker of the progression of Parkinsons disease is analyzed. (1 figure, bibliography: 62 refs)

Sign in / Sign up

Export Citation Format

Share Document