The Experts below are selected from a list of 20295 Experts worldwide ranked by ideXlab platform
Claudio Soto - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Protein Misfolding and aggregation by natural phenolic compounds
Cellular and Molecular Life Sciences, 2018Co-Authors: Zohra Dhouafli, Karina Cuanalo-contreras, Claudio Soto, El Akrem Hayouni, Charles E. Mays, Ines Moreno-gonzalezAbstract:Protein Misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed Protein Misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer’s and Parkinson’s diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover Protein Misfolding inhibitors that might be useful for the treatment of various incurable diseases.
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Protein Misfolding, aggregation, and conformational strains in neurodegenerative diseases.
Nature Neuroscience, 2018Co-Authors: Claudio Soto, Sandra PritzkowAbstract:A hallmark event in neurodegenerative diseases (NDs) is the Misfolding, aggregation, and accumulation of Proteins, leading to cellular dysfunction, loss of synaptic connections, and brain damage. Despite the involvement of distinct Proteins in different NDs, the process of Protein Misfolding and aggregation is remarkably similar. A recent breakthrough in the field was the discovery that misfolded Protein aggregates can self-propagate through seeding and spread the pathological abnormalities between cells and tissues in a manner akin to the behavior of infectious prions in prion diseases. This discovery has vast implications for understanding the mechanisms involved in the initiation and progression of NDs, as well as for the design of novel strategies for treatment and diagnosis. In this Review, we provide a critical discussion of the role of Protein Misfolding and aggregation in NDs. Commonalities and differences between distinct Protein aggregates will be highlighted, in addition to evidence supporting the hypothesis that misfolded aggregates can be transmissible by the prion principle. We will also describe the molecular basis and implications for prion-like conformational strains, cross-interaction between different misfolded Proteins in the brain, and how these concepts can be applied to the development of novel strategies for therapy and diagnosis.
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Type 2 diabetes as a Protein Misfolding disease
Trends in Molecular Medicine, 2015Co-Authors: Abhisek Mukherjee, Diego Morales-scheihing, Peter C. Butler, Claudio SotoAbstract:Type 2 diabetes (T2D) is a highly prevalent and chronic metabolic disorder. Recent evidence suggests that formation of toxic aggregates of the islet amyloid polypeptide (IAPP) might contribute to β-cell dysfunction and disease. However, the mechanism of Protein aggregation and associated toxicity remains unclear. Misfolding, aggregation, and accumulation of diverse Proteins in various organs is the hallmark of the group of Protein Misfolding disorders (PMDs), including highly prevalent illnesses affecting the central nervous system (CNS) such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this review we discuss the current understanding of the mechanisms implicated in the formation of Protein aggregates in the endocrine pancreas and associated toxicity in the light of the long-standing knowledge from neurodegenerative disorders associated with Protein Misfolding.
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Role of Protein Misfolding and Proteostasis Deficiency in Protein Misfolding Diseases and Aging
International Journal of Cell Biology, 2013Co-Authors: Karina Cuanalo-contreras, Abhisek Mukherjee, Claudio SotoAbstract:The Misfolding, aggregation, and tissue accumulation of Proteins are common events in diverse chronic diseases, known as Protein Misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of Protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether Protein Misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain Protein homeostasis. These protective pathways include the unfolded Protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged Proteins in aggresomes. In this paper we review the current knowledge on the role of Protein Misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in Protein Misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent Protein Misfolding disorders and perhaps aging itself.
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Protein Misfolding cyclic amplification
Prions and Diseases, 2012Co-Authors: Fabio Moda, Sandra Pritzkow, Claudio SotoAbstract:Prion diseases are caused by a conformational conversion of the cellular prion Protein (PrPC) to a pathological conformer (PrPSc). The “prion-only” hypothesis suggests that PrPSc is the infectious agent that propagates the disease acting as a template for the conversion of PrPC. In 2001, we developed a novel in vitro technique, called Protein Misfolding cyclic amplification (PMCA), which mimics this pathological process in an accelerated way. Thereby, minimal amount of PrPSc can be amplified to several millions fold, providing an important tool for diagnosis and investigation of prion biology, and the molecular mechanism of prion conversion. PMCA also offers a great platform for the study and amplification of the Protein Misfolding process associated with other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases.
Stuart A. Lipton - One of the best experts on this subject based on the ideXlab platform.
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Redox Reactions Induced by Nitrosative Stress Mediate Protein Misfolding and Mitochondrial Dysfunction in Neurodegenerative Diseases
Molecular Neurobiology, 2010Co-Authors: Zezong Gu, Tomohiro Nakamura, Stuart A. LiptonAbstract:Overstimulation of N -methyl- d -aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic diseases. Neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD), manifest deposits of misfolded or aggregated Proteins, and result from synaptic injury and neuronal death. Recent studies have suggested that nitrosative stress due to generation of excessive nitric oxide (NO) can mediate excitotoxicity in part by triggering Protein Misfolding and aggregation, and mitochondrial fragmentation in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific Protein thiol groups, represents a convergent signal pathway contributing to NO-induced Protein Misfolding and aggregation, compromised dynamics of mitochondrial fission-fusion process, thus leading to neurotoxicity. Here, we review the effect of S-nitrosylation on Protein function under excitotoxic conditions, and present evidence suggesting that NO contributes to Protein Misfolding and aggregation via S-nitrosylating Protein-disulfide isomerase or the E3 ubiquitin ligase parkin, and mitochondrial fragmentation through β-amyloid-related S-nitrosylation of dynamin-related Protein-1. Moreover, we also discuss that inhibition of excessive NMDA receptor activity by memantine, an uncompetitive/fast off-rate (UFO) drug can ameliorate excessive production of NO, Protein Misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration.
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Redox reactions induced by nitrosative stress mediate Protein Misfolding and mitochondrial dysfunction in neurodegenerative diseases.
Molecular Neurobiology, 2010Co-Authors: Tomohiro Nakamura, Stuart A. LiptonAbstract:Overstimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic diseases. Neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD), manifest deposits of misfolded or aggregated Proteins, and result from synaptic injury and neuronal death. Recent studies have suggested that nitrosative stress due to generation of excessive nitric oxide (NO) can mediate excitotoxicity in part by triggering Protein Misfolding and aggregation, and mitochondrial fragmentation in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific Protein thiol groups, represents a convergent signal pathway contributing to NO-induced Protein Misfolding and aggregation, compromised dynamics of mitochondrial fission-fusion process, thus leading to neurotoxicity. Here, we review the effect of S-nitrosylation on Protein function under excitotoxic conditions, and present evidence suggesting that NO contributes to Protein Misfolding and aggregation via S-nitrosylating Protein-disulfide isomerase or the E3 ubiquitin ligase parkin, and mitochondrial fragmentation through beta-amyloid-related S-nitrosylation of dynamin-related Protein-1. Moreover, we also discuss that inhibition of excessive NMDA receptor activity by memantine, an uncompetitive/fast off-rate (UFO) drug can ameliorate excessive production of NO, Protein Misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration.
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Cell death: Protein Misfolding and neurodegenerative diseases
Apoptosis, 2009Co-Authors: Tomohiro Nakamura, Stuart A. LiptonAbstract:Several chronic neurodegenerative disorders manifest deposits of misfolded or aggregated Proteins. Genetic mutations are the root cause for Protein Misfolding in rare families, but the majority of patients have sporadic forms possibly related to environmental factors. In some cases, the ubiquitin-proteasome system or molecular chaperones can prevent accumulation of aberrantly folded Proteins. Recent studies suggest that generation of excessive nitric oxide (NO) and reactive oxygen species (ROS), in part due to overactivity of the NMDA-subtype of glutamate receptor, can mediate Protein Misfolding in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific Protein thiol groups, represents one mechanism contributing to NO-induced Protein Misfolding and neurotoxicity. Here, we present evidence suggesting that NO contributes to Protein Misfolding via S-nitrosylating Protein-disulfide isomerase or the E3 ubiquitin ligase parkin. We discuss how memantine/NitroMemantine can inhibit excessive NMDA receptor activity to ameliorate NO production, Protein Misfolding, and neurodegeneration.
Vladimir N Uversky - One of the best experts on this subject based on the ideXlab platform.
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Bio-nanoimaging: Protein Misfolding and Aggregation
2014Co-Authors: Vladimir N Uversky, Yuri L LyubchenkoAbstract:Part 1. Nanotechnology and nanoimaging of aggregating Proteins Nanoimaging of aggregated Proteins Cryoelectron microscopy of beta(2)-microglobulin Amyloid fibril length quantification by AFM Seeing fibril formation in real time Studying amyloidogensis by FRET Structure, growth and assembly of amyloid-like fibrils using high-speed atomic force microscopy Analyzing amyloid fibril structure by scanning transmission electron microscopy Magic angle spinning NMR of amyloid fibrils Analyzing Protein deposits in vivo by confocal laser multiphoton laser scanning microscopy Amyloid imaging agents Reporters of amyloid structure Immunohistochemical detection of amyloid components Scanning tunneling microscopy of Protein deposits Probing of Protein Misfolding with single molecule force spectroscopy Single molecule characterization of -synuclein in aggregation-prone states Part 2. Polymorphism of Protein misfolded and aggregated species Fibrillar polymorphism Ab fibril polymorphism Prefibrillar Ab oligomers Structural heterogeneity of in vitro and ex vivo amyloid assemblies Polymorphism of tau fibrils Amyloid-like protofibrils with different physical properties Micelle-Like Architecture of the Amyloid- Peptide Insulin oligomers Worm-like amyloid fibrils of mouse prion Protein ApolipoProtein C-II Amyloid Fibrils Amylin oligomers and fibrils Amyloid fibrils of human stefins Fibrillar structure of Sup35 in vivo Dopamine-induced -synuclein oligomers Amyloid spherulites A stable lipid-induced aggregate of alpha-synuclein Part 3. Polymorphism of Protein Misfolding and aggregation processes Multiple pathways of lysozyme aggregation Structure-function study of amyloid ion channels in neurodegenerative diseases Amyloid -Protein assembly Molecular mechanisms underlying alpha synucelin misassembly Multiple pathways of amyloid assembly /disassembly studied by AFM Sequestering of metastable Proteins with essential cellular functions by amyloid-like aggregates Misfolded intermediate of a PDZ domain Structural characterization of the amyloidogenic state of human lysozyme Landscape Model of Filamentous Protein Aggregation Micelle formation by human islet amyloid polypeptide Effect of anionic polysaccharide on -lactoglobulin fibrillation
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Nanoimaging in Protein-Misfolding and -conformational diseases.
Nanomedicine, 2007Co-Authors: Vladimir N UverskyAbstract:Protein Misfolding and the subsequent assembly of Protein molecules into aggregates of various morphologies represent common mechanisms that link a number of important human diseases, known as Protein-Misfolding diseases. The current list of these disorders includes (but is not limited to) numerous neurodegenerative diseases, cataracts, arthritis, medullary carcinoma of the thyroid, late-onset diabetes mellitus, symptomatic (hemodialysis-related) β2-microglobulin amyloidosis, arthritis and many other systemic, localized and familial amyloidoses. Progress in understanding Protein-Misfolding pathologies and in potential rational drug design aimed at the inhibition or reversal of Protein aggregation depends on our ability to study the details of the Misfolding process, to follow the aggregation process and to see and analyze the structure and mechanical properties of the aggregated particles. Nanoimaging provides a method to monitor the aggregation process, visualize Protein aggregates and analyze their prop...
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nanotools for megaproblems probing Protein Misfolding diseases using nanomedicine modus operandi
Journal of Proteome Research, 2006Co-Authors: Vladimir N Uversky, And Alexander V Kabanov, Yuri L LyubchenkoAbstract:Misfolding and self-assembly of Proteins in nanoaggregates of different sizes and morphologies (nanoensembles, primary nanofilaments, nanorings, filaments, protofibrils, fibrils, etc.) is a common theme unifying a number of human pathologies termed Protein Misfolding diseases. Recent studies highlight increasing recognition of the public health importance of Protein Misfolding diseases, including various neurodegenerative disorders and amyloidoses. It is understood now that the first essential elements in the vast majority of neurodegenerative processes are misfolded and aggregated Proteins. Altogether, the accumulation of abnormal Protein nanoensembles exerts toxicity by disrupting intracellular transport, overwhelming Protein degradation pathways, and/or disturbing vital cell functions. In addition, the formation of inclusion bodies is known to represent a major problem in the production of recombinant therapeutic Proteins. Formulation of these therapeutic Proteins into delivery systems and their in vivo delivery are often complicated by Protein association. Thus, Protein folding abnormalities and subsequent events underlie a multitude of human pathologies and difficulties with Protein therapeutic applications. The field of medicine therefore can be greatly advanced by establishing a fundamental understanding of key factors leading to Misfolding and self-assembly responsible for various Protein folding pathologies. This article overviews Protein Misfolding diseases and outlines some novel and advanced nanotechnologies, including nanoimaging techniques, nanotoolboxes and nanocontainers, complemented by appropriate ensemble techniques, all focused on the ultimate goal to establish etiology and to diagnose, prevent, and cure these devastating disorders.
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Nanoimaging for Protein Misfolding and related diseases
Journal of Cellular Biochemistry, 2006Co-Authors: Yuri L Lyubchenko, Simon Sherman, Luda S. Shlyakhtenko, Vladimir N UverskyAbstract:Misfolding and aggregation of Proteins is a common thread linking a number of important human health problems. The misfolded and aggregated Proteins are inducers of cellular stress and activators of immunity in neurodegenerative diseases. They might possess clear cytotoxic properties, being responsible for the dysfunction and loss of cells in the affected organs. Despite the crucial importance of Protein Misfolding and abnormal interactions, very little is currently known about the molecular mechanism underlying these processes. Factors that lead to Protein Misfolding and aggregation in vitro are poorly understood, not to mention the complexities involved in the formation of Protein nanoparticles with different morphologies (e.g., the nanopores) in vivo. A better understanding of the molecular mechanisms of Misfolding and aggregation might facilitate development of the rational approaches to prevent pathologies mediated by Protein Misfolding. The conventional tools currently available to researchers can only provide an averaged picture of a living system, whereas much of the subtle or short-lived information is lost. We believe that the existing and emerging nanotools might help solving these problems by opening the entirely novel pathways for the development of early diagnostic and therapeutic approaches. This article summarizes recent advances of the nanoscience in detection and characterization of misfolded Protein conformations. Based on these findings, we outline our view on the nanoscience development towards identification intracellular nanomachines and/or multicomponent complexes critically involved in Protein Misfolding.
Yuri L Lyubchenko - One of the best experts on this subject based on the ideXlab platform.
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Bio-nanoimaging: Protein Misfolding and Aggregation
2014Co-Authors: Vladimir N Uversky, Yuri L LyubchenkoAbstract:Part 1. Nanotechnology and nanoimaging of aggregating Proteins Nanoimaging of aggregated Proteins Cryoelectron microscopy of beta(2)-microglobulin Amyloid fibril length quantification by AFM Seeing fibril formation in real time Studying amyloidogensis by FRET Structure, growth and assembly of amyloid-like fibrils using high-speed atomic force microscopy Analyzing amyloid fibril structure by scanning transmission electron microscopy Magic angle spinning NMR of amyloid fibrils Analyzing Protein deposits in vivo by confocal laser multiphoton laser scanning microscopy Amyloid imaging agents Reporters of amyloid structure Immunohistochemical detection of amyloid components Scanning tunneling microscopy of Protein deposits Probing of Protein Misfolding with single molecule force spectroscopy Single molecule characterization of -synuclein in aggregation-prone states Part 2. Polymorphism of Protein misfolded and aggregated species Fibrillar polymorphism Ab fibril polymorphism Prefibrillar Ab oligomers Structural heterogeneity of in vitro and ex vivo amyloid assemblies Polymorphism of tau fibrils Amyloid-like protofibrils with different physical properties Micelle-Like Architecture of the Amyloid- Peptide Insulin oligomers Worm-like amyloid fibrils of mouse prion Protein ApolipoProtein C-II Amyloid Fibrils Amylin oligomers and fibrils Amyloid fibrils of human stefins Fibrillar structure of Sup35 in vivo Dopamine-induced -synuclein oligomers Amyloid spherulites A stable lipid-induced aggregate of alpha-synuclein Part 3. Polymorphism of Protein Misfolding and aggregation processes Multiple pathways of lysozyme aggregation Structure-function study of amyloid ion channels in neurodegenerative diseases Amyloid -Protein assembly Molecular mechanisms underlying alpha synucelin misassembly Multiple pathways of amyloid assembly /disassembly studied by AFM Sequestering of metastable Proteins with essential cellular functions by amyloid-like aggregates Misfolded intermediate of a PDZ domain Structural characterization of the amyloidogenic state of human lysozyme Landscape Model of Filamentous Protein Aggregation Micelle formation by human islet amyloid polypeptide Effect of anionic polysaccharide on -lactoglobulin fibrillation
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nanotools for megaproblems probing Protein Misfolding diseases using nanomedicine modus operandi
Journal of Proteome Research, 2006Co-Authors: Vladimir N Uversky, And Alexander V Kabanov, Yuri L LyubchenkoAbstract:Misfolding and self-assembly of Proteins in nanoaggregates of different sizes and morphologies (nanoensembles, primary nanofilaments, nanorings, filaments, protofibrils, fibrils, etc.) is a common theme unifying a number of human pathologies termed Protein Misfolding diseases. Recent studies highlight increasing recognition of the public health importance of Protein Misfolding diseases, including various neurodegenerative disorders and amyloidoses. It is understood now that the first essential elements in the vast majority of neurodegenerative processes are misfolded and aggregated Proteins. Altogether, the accumulation of abnormal Protein nanoensembles exerts toxicity by disrupting intracellular transport, overwhelming Protein degradation pathways, and/or disturbing vital cell functions. In addition, the formation of inclusion bodies is known to represent a major problem in the production of recombinant therapeutic Proteins. Formulation of these therapeutic Proteins into delivery systems and their in vivo delivery are often complicated by Protein association. Thus, Protein folding abnormalities and subsequent events underlie a multitude of human pathologies and difficulties with Protein therapeutic applications. The field of medicine therefore can be greatly advanced by establishing a fundamental understanding of key factors leading to Misfolding and self-assembly responsible for various Protein folding pathologies. This article overviews Protein Misfolding diseases and outlines some novel and advanced nanotechnologies, including nanoimaging techniques, nanotoolboxes and nanocontainers, complemented by appropriate ensemble techniques, all focused on the ultimate goal to establish etiology and to diagnose, prevent, and cure these devastating disorders.
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Nanoimaging for Protein Misfolding and related diseases
Journal of Cellular Biochemistry, 2006Co-Authors: Yuri L Lyubchenko, Simon Sherman, Luda S. Shlyakhtenko, Vladimir N UverskyAbstract:Misfolding and aggregation of Proteins is a common thread linking a number of important human health problems. The misfolded and aggregated Proteins are inducers of cellular stress and activators of immunity in neurodegenerative diseases. They might possess clear cytotoxic properties, being responsible for the dysfunction and loss of cells in the affected organs. Despite the crucial importance of Protein Misfolding and abnormal interactions, very little is currently known about the molecular mechanism underlying these processes. Factors that lead to Protein Misfolding and aggregation in vitro are poorly understood, not to mention the complexities involved in the formation of Protein nanoparticles with different morphologies (e.g., the nanopores) in vivo. A better understanding of the molecular mechanisms of Misfolding and aggregation might facilitate development of the rational approaches to prevent pathologies mediated by Protein Misfolding. The conventional tools currently available to researchers can only provide an averaged picture of a living system, whereas much of the subtle or short-lived information is lost. We believe that the existing and emerging nanotools might help solving these problems by opening the entirely novel pathways for the development of early diagnostic and therapeutic approaches. This article summarizes recent advances of the nanoscience in detection and characterization of misfolded Protein conformations. Based on these findings, we outline our view on the nanoscience development towards identification intracellular nanomachines and/or multicomponent complexes critically involved in Protein Misfolding.
Tomohiro Nakamura - One of the best experts on this subject based on the ideXlab platform.
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Redox Reactions Induced by Nitrosative Stress Mediate Protein Misfolding and Mitochondrial Dysfunction in Neurodegenerative Diseases
Molecular Neurobiology, 2010Co-Authors: Zezong Gu, Tomohiro Nakamura, Stuart A. LiptonAbstract:Overstimulation of N -methyl- d -aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic diseases. Neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD), manifest deposits of misfolded or aggregated Proteins, and result from synaptic injury and neuronal death. Recent studies have suggested that nitrosative stress due to generation of excessive nitric oxide (NO) can mediate excitotoxicity in part by triggering Protein Misfolding and aggregation, and mitochondrial fragmentation in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific Protein thiol groups, represents a convergent signal pathway contributing to NO-induced Protein Misfolding and aggregation, compromised dynamics of mitochondrial fission-fusion process, thus leading to neurotoxicity. Here, we review the effect of S-nitrosylation on Protein function under excitotoxic conditions, and present evidence suggesting that NO contributes to Protein Misfolding and aggregation via S-nitrosylating Protein-disulfide isomerase or the E3 ubiquitin ligase parkin, and mitochondrial fragmentation through β-amyloid-related S-nitrosylation of dynamin-related Protein-1. Moreover, we also discuss that inhibition of excessive NMDA receptor activity by memantine, an uncompetitive/fast off-rate (UFO) drug can ameliorate excessive production of NO, Protein Misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration.
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Redox reactions induced by nitrosative stress mediate Protein Misfolding and mitochondrial dysfunction in neurodegenerative diseases.
Molecular Neurobiology, 2010Co-Authors: Tomohiro Nakamura, Stuart A. LiptonAbstract:Overstimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic diseases. Neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD), manifest deposits of misfolded or aggregated Proteins, and result from synaptic injury and neuronal death. Recent studies have suggested that nitrosative stress due to generation of excessive nitric oxide (NO) can mediate excitotoxicity in part by triggering Protein Misfolding and aggregation, and mitochondrial fragmentation in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific Protein thiol groups, represents a convergent signal pathway contributing to NO-induced Protein Misfolding and aggregation, compromised dynamics of mitochondrial fission-fusion process, thus leading to neurotoxicity. Here, we review the effect of S-nitrosylation on Protein function under excitotoxic conditions, and present evidence suggesting that NO contributes to Protein Misfolding and aggregation via S-nitrosylating Protein-disulfide isomerase or the E3 ubiquitin ligase parkin, and mitochondrial fragmentation through beta-amyloid-related S-nitrosylation of dynamin-related Protein-1. Moreover, we also discuss that inhibition of excessive NMDA receptor activity by memantine, an uncompetitive/fast off-rate (UFO) drug can ameliorate excessive production of NO, Protein Misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration.
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Cell death: Protein Misfolding and neurodegenerative diseases
Apoptosis, 2009Co-Authors: Tomohiro Nakamura, Stuart A. LiptonAbstract:Several chronic neurodegenerative disorders manifest deposits of misfolded or aggregated Proteins. Genetic mutations are the root cause for Protein Misfolding in rare families, but the majority of patients have sporadic forms possibly related to environmental factors. In some cases, the ubiquitin-proteasome system or molecular chaperones can prevent accumulation of aberrantly folded Proteins. Recent studies suggest that generation of excessive nitric oxide (NO) and reactive oxygen species (ROS), in part due to overactivity of the NMDA-subtype of glutamate receptor, can mediate Protein Misfolding in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific Protein thiol groups, represents one mechanism contributing to NO-induced Protein Misfolding and neurotoxicity. Here, we present evidence suggesting that NO contributes to Protein Misfolding via S-nitrosylating Protein-disulfide isomerase or the E3 ubiquitin ligase parkin. We discuss how memantine/NitroMemantine can inhibit excessive NMDA receptor activity to ameliorate NO production, Protein Misfolding, and neurodegeneration.
