Pub Date : 2003-11-30DOI: 10.2174/1568013033483249
B. J. Tabner, S. Turnbull, O. El‐Agnaf, D. Allsop
The deposition of abnormal protein fibrils is a prominent pathological feature of many different ‘protein conformational’ diseases, including some important neurodegenerative diseases. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the b-amyloid (Ab) peptide, which accumulates in the brain in Alzheimer’s disease, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown that solutions of Ab liberate hydroxyl radicals when incubated in vitro, upon the addition of small amounts of Fe(II). We have also obtained similar results with a-synuclein, which accumulates in Lewy bodies in Parkinson’s disease, and with the PrP (106-126) toxic fragment of the prion protein. It is becoming clear that some transition metal ions, especially Fe(III) and Cu(II), can bind to these aggregating peptides, and that some of them can reduce the oxidation state of Fe(III) and/or Cu(II). The data suggest that hydrogen peroxide accumulates during incubation of these various proteins and peptides, and is subsequently converted to hydroxyl radicals in the presence of redox-active transition metal ions. Consequently, a fundamental molecular mechanism underlying the pathogenesis of cell death in several different neurodegenerative diseases could be the direct production of ROS during formation of the abnormal protein aggregates.
{"title":"Direct production of reactive oxygen species from aggregating proteins and peptides implicated in the pathogenesis of neurodegenerative diseases.","authors":"B. J. Tabner, S. Turnbull, O. El‐Agnaf, D. Allsop","doi":"10.2174/1568013033483249","DOIUrl":"https://doi.org/10.2174/1568013033483249","url":null,"abstract":"The deposition of abnormal protein fibrils is a prominent pathological feature of many different ‘protein conformational’ diseases, including some important neurodegenerative diseases. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the b-amyloid (Ab) peptide, which accumulates in the brain in Alzheimer’s disease, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown that solutions of Ab liberate hydroxyl radicals when incubated in vitro, upon the addition of small amounts of Fe(II). We have also obtained similar results with a-synuclein, which accumulates in Lewy bodies in Parkinson’s disease, and with the PrP (106-126) toxic fragment of the prion protein. It is becoming clear that some transition metal ions, especially Fe(III) and Cu(II), can bind to these aggregating peptides, and that some of them can reduce the oxidation state of Fe(III) and/or Cu(II). The data suggest that hydrogen peroxide accumulates during incubation of these various proteins and peptides, and is subsequently converted to hydroxyl radicals in the presence of redox-active transition metal ions. Consequently, a fundamental molecular mechanism underlying the pathogenesis of cell death in several different neurodegenerative diseases could be the direct production of ROS during formation of the abnormal protein aggregates.","PeriodicalId":88234,"journal":{"name":"Current medicinal chemistry. Immunology, endocrine & metabolic agents","volume":"3 1","pages":"299-308"},"PeriodicalIF":0.0,"publicationDate":"2003-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67895199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2003-11-30DOI: 10.2174/1568013033483294
F. Gervais, C. Morissette, X. Kong
Amyloidogenic proteins have the characteristic of adopting a β-sheet conformation and assembling into fibrils. Although similar in fibrillar appearance, each type of peripheral amyloid deposits differs in the nature of the amyloidogenic protein forming fibrils. Other elements, known as the common structural elements of the amyloid deposits, also contribute to amyloidogenic process in vivo. Among these elements, heparan sulfate proteoglycans (HSPGs) have been shown to bind to different types of amyloidogenic proteins and to promote the formation of β-sheet secondary structure. Once fibrils are formed, HSPGs protect the fibrils from proteolytic degradation, which lead to the accumulation of the deposits in the targeted organs. Understanding the regulation of protein folding by proteoglycans can lead to the development of low molecular weight compounds, which bind to the amyloidogenic proteins prior to their organization as fibrils. Such binding would interfere with the natural association of amyloidogenic protein with HSPGs and maintain the amyloid protein in a non-fibrillar structure (either random coil or a mix of α-helix and β-sheet structure). It would also favor their clearance, and thereby inhibit or completely block the formation of amyloid deposits. Since HSPGs interact with several types of amyloidogenic proteins, such an approach may be beneficial for the treatment of systemic and localized types of amyloidosis.
{"title":"Proteoglycans and Amyloidogenic Proteins in Peripheral Amyloidosis","authors":"F. Gervais, C. Morissette, X. Kong","doi":"10.2174/1568013033483294","DOIUrl":"https://doi.org/10.2174/1568013033483294","url":null,"abstract":"Amyloidogenic proteins have the characteristic of adopting a β-sheet conformation and assembling into fibrils. Although similar in fibrillar appearance, each type of peripheral amyloid deposits differs in the nature of the amyloidogenic protein forming fibrils. Other elements, known as the common structural elements of the amyloid deposits, also contribute to amyloidogenic process in vivo. Among these elements, heparan sulfate proteoglycans (HSPGs) have been shown to bind to different types of amyloidogenic proteins and to promote the formation of β-sheet secondary structure. Once fibrils are formed, HSPGs protect the fibrils from proteolytic degradation, which lead to the accumulation of the deposits in the targeted organs. Understanding the regulation of protein folding by proteoglycans can lead to the development of low molecular weight compounds, which bind to the amyloidogenic proteins prior to their organization as fibrils. Such binding would interfere with the natural association of amyloidogenic protein with HSPGs and maintain the amyloid protein in a non-fibrillar structure (either random coil or a mix of α-helix and β-sheet structure). It would also favor their clearance, and thereby inhibit or completely block the formation of amyloid deposits. Since HSPGs interact with several types of amyloidogenic proteins, such an approach may be beneficial for the treatment of systemic and localized types of amyloidosis.","PeriodicalId":88234,"journal":{"name":"Current medicinal chemistry. Immunology, endocrine & metabolic agents","volume":"3 1","pages":"361-370"},"PeriodicalIF":0.0,"publicationDate":"2003-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67896491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2003-11-30DOI: 10.2174/1568013033483221
Hyoung-Gon Lee, Xiongwei Zhu, R. Petersen, George Perry, Mark A. Smith
Protein aggregation and misfolding are two of the pathological hallmarks that are common to many neurodegenerative diseases including Alzheimer disease, Parkinson disease and Huntington disease. While it has generally been assumed that protein aggregation is responsible for neurodegeneration in these disorders, we suspect that protein aggregation, rather than being a major killer of neurons, is, in fact, an attempt to protect neurons from stressful, disease-causing conditions. In this review, we weigh the evidence of whether amyloids, aggregates and neuronal inclusions are good or bad news for neurons.
{"title":"Amyloids, Aggregates and Neuronal Inclusions: Good or Bad News for Neurons?","authors":"Hyoung-Gon Lee, Xiongwei Zhu, R. Petersen, George Perry, Mark A. Smith","doi":"10.2174/1568013033483221","DOIUrl":"https://doi.org/10.2174/1568013033483221","url":null,"abstract":"Protein aggregation and misfolding are two of the pathological hallmarks that are common to many neurodegenerative diseases including Alzheimer disease, Parkinson disease and Huntington disease. While it has generally been assumed that protein aggregation is responsible for neurodegeneration in these disorders, we suspect that protein aggregation, rather than being a major killer of neurons, is, in fact, an attempt to protect neurons from stressful, disease-causing conditions. In this review, we weigh the evidence of whether amyloids, aggregates and neuronal inclusions are good or bad news for neurons.","PeriodicalId":88234,"journal":{"name":"Current medicinal chemistry. Immunology, endocrine & metabolic agents","volume":"3 1","pages":"293-298"},"PeriodicalIF":0.0,"publicationDate":"2003-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568013033483221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67895673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2003-11-30DOI: 10.2174/1568013033483267
R. Kalaria, Alan J. Thomas, A. Oakley, P. Ince, A. Tamaoka, H. Mori, R. Kenny, C. Ballard
Cerebrovascular amyloidosis occurs increasingly in older age. The amyloid β (Aβ) protein type of cerebral amyloid angiopathy (CAA) is the most common form of this microangiopathy, evident in virtually all cases of Alzheimer’s disease (AD). CAA may range from focal deposits to widespread infiltration of amyloid in walls of perforating and meningeal arteries, capillaries and diffuse perivascular plaques. Prior to their degeneration vascular smooth muscle cells may be sensitised and stimulated by the aggregated amyloid peptide itself and cytokines. Two patterns of CAA namely arteriolar and capillary types have recently been recognized. CAA also occurs in other dementing conditions including Down’s syndrome and dementia with Lewy bodies. It is the principal feature of the hereditary amyloid angiopathies such as hereditary cerberal haemorrhage with amyloidosis of the Dutch type and familial British dementia. Varying degrees of CAA have been recorded in early onset familial AD. Mutations in the amyloid precursor protein (APP) gene that lie in codons within the Aβ domain may result in a phenotype characterised by severe CAA, cerebral infarction and white matter disease. The apolipoprotein E e4 allele is a strong factor in the development of Aβ CAA, which may progress to lobar or intracerebral hemorrhages. At least two different transgenic mice models over-expressing human APP implicate neuronal origin of the Aβ within vascular deposits. CAA may largely develop due to lack of clearance by reduced proteolytic degradation and progressive blockage of the interstitial drainage pathways via the brain vascular routes superimposed by age-related arteriosclerotic changes. Current observations from both sporadic and familial cases suggest CAA to be an independent factor for cognitive impairment and dementia.
{"title":"Cerebrovascular Amyloidosis and Dementia","authors":"R. Kalaria, Alan J. Thomas, A. Oakley, P. Ince, A. Tamaoka, H. Mori, R. Kenny, C. Ballard","doi":"10.2174/1568013033483267","DOIUrl":"https://doi.org/10.2174/1568013033483267","url":null,"abstract":"Cerebrovascular amyloidosis occurs increasingly in older age. The amyloid β (Aβ) protein type of cerebral amyloid angiopathy (CAA) is the most common form of this microangiopathy, evident in virtually all cases of Alzheimer’s disease (AD). CAA may range from focal deposits to widespread infiltration of amyloid in walls of perforating and meningeal arteries, capillaries and diffuse perivascular plaques. Prior to their degeneration vascular smooth muscle cells may be sensitised and stimulated by the aggregated amyloid peptide itself and cytokines. Two patterns of CAA namely arteriolar and capillary types have recently been recognized. CAA also occurs in other dementing conditions including Down’s syndrome and dementia with Lewy bodies. It is the principal feature of the hereditary amyloid angiopathies such as hereditary cerberal haemorrhage with amyloidosis of the Dutch type and familial British dementia. Varying degrees of CAA have been recorded in early onset familial AD. Mutations in the amyloid precursor protein (APP) gene that lie in codons within the Aβ domain may result in a phenotype characterised by severe CAA, cerebral infarction and white matter disease. The apolipoprotein E e4 allele is a strong factor in the development of Aβ CAA, which may progress to lobar or intracerebral hemorrhages. At least two different transgenic mice models over-expressing human APP implicate neuronal origin of the Aβ within vascular deposits. CAA may largely develop due to lack of clearance by reduced proteolytic degradation and progressive blockage of the interstitial drainage pathways via the brain vascular routes superimposed by age-related arteriosclerotic changes. Current observations from both sporadic and familial cases suggest CAA to be an independent factor for cognitive impairment and dementia.","PeriodicalId":88234,"journal":{"name":"Current medicinal chemistry. Immunology, endocrine & metabolic agents","volume":"3 1","pages":"317-327"},"PeriodicalIF":0.0,"publicationDate":"2003-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67895328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2003-11-30DOI: 10.2174/1568013033483230
R. Brito, A. Damas, M. Saraiva
In recent years the issues of protein stability, folding and aggregation have become central in several pathological conditions and in particular in amyloid diseases. Here, we review the recent developments on the molecular mechanisms of amyloid formation by transthyretin (TTR), in particular, in what concerns to protein conformational stability, protein folding and aggregation. Transthyretin has been implicated in pathologies such as senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC) which are characterized by extracellular deposition of insoluble amyloid fibrils. SSA is generally a mild disorder and affects predominantly individuals over 80 years of age. In contrast, FAP is an autossomal dominant lethal disease, characterized by peripheral neuropathy, which may affect individuals from their twenties. While in SSA WT-TTR and its fragments are the major constituents of the amyloid fibrils, in FAP and FAC the amyloid fibrils are mostly constituted by variants of TTR. Today, more than 80 amyloidogenic TTR mutations throughout the TTR sequence are known. Transthyretin is a homotetrameric protein found in the plasma and in the cerebral-spinal fluid, it is synthesized in the liver and in the choroid plexus of the brain, it has a total molecular mass of 55kDa and a high percentage of β-sheet. Current views on amyloid fibril formation by TTR state that, depending on the protein variant or solution conditions, the native tetrameric protein might dissociate to non-native or partially unfolded monomeric (or even dimeric) species with a high tendency for ordered aggregation into soluble oligomers which grow into insoluble oligomers and eventually mature amyloid fibrils. Thus, issues such as dissociation thermodynamics and dissociation kinetics of the native tetrameric TTR and thermodynamic stability and conformational fluctuations of the non-native TTR molecular species are essential in determining the amyloidogenic potential of different TTR variants. In addition, several other cellular and tissue factors must be involved in modulating the penetrance and age of onset of amyloid pathologies by TTR.
{"title":"Amyloid Formation by Transthyretin: From Protein Stability to Protein Aggregation","authors":"R. Brito, A. Damas, M. Saraiva","doi":"10.2174/1568013033483230","DOIUrl":"https://doi.org/10.2174/1568013033483230","url":null,"abstract":"In recent years the issues of protein stability, folding and aggregation have become central in several pathological conditions and in particular in amyloid diseases. Here, we review the recent developments on the molecular mechanisms of amyloid formation by transthyretin (TTR), in particular, in what concerns to protein conformational stability, protein folding and aggregation. Transthyretin has been implicated in pathologies such as senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC) which are characterized by extracellular deposition of insoluble amyloid fibrils. SSA is generally a mild disorder and affects predominantly individuals over 80 years of age. In contrast, FAP is an autossomal dominant lethal disease, characterized by peripheral neuropathy, which may affect individuals from their twenties. While in SSA WT-TTR and its fragments are the major constituents of the amyloid fibrils, in FAP and FAC the amyloid fibrils are mostly constituted by variants of TTR. Today, more than 80 amyloidogenic TTR mutations throughout the TTR sequence are known. Transthyretin is a homotetrameric protein found in the plasma and in the cerebral-spinal fluid, it is synthesized in the liver and in the choroid plexus of the brain, it has a total molecular mass of 55kDa and a high percentage of β-sheet. Current views on amyloid fibril formation by TTR state that, depending on the protein variant or solution conditions, the native tetrameric protein might dissociate to non-native or partially unfolded monomeric (or even dimeric) species with a high tendency for ordered aggregation into soluble oligomers which grow into insoluble oligomers and eventually mature amyloid fibrils. Thus, issues such as dissociation thermodynamics and dissociation kinetics of the native tetrameric TTR and thermodynamic stability and conformational fluctuations of the non-native TTR molecular species are essential in determining the amyloidogenic potential of different TTR variants. In addition, several other cellular and tissue factors must be involved in modulating the penetrance and age of onset of amyloid pathologies by TTR.","PeriodicalId":88234,"journal":{"name":"Current medicinal chemistry. Immunology, endocrine & metabolic agents","volume":"3 1","pages":"349-360"},"PeriodicalIF":0.0,"publicationDate":"2003-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67895721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2003-08-31DOI: 10.2174/1568013033483375
T. Fujino, Y. Ikeda, T. Osborne, Sadao Takahashi, Tokuo T. Yamamoto, J. Sakai
{"title":"Sources of Acetyl-CoA: Acetyl-CoA Synthetase 1 and 2","authors":"T. Fujino, Y. Ikeda, T. Osborne, Sadao Takahashi, Tokuo T. Yamamoto, J. Sakai","doi":"10.2174/1568013033483375","DOIUrl":"https://doi.org/10.2174/1568013033483375","url":null,"abstract":"","PeriodicalId":88234,"journal":{"name":"Current medicinal chemistry. Immunology, endocrine & metabolic agents","volume":"3 1","pages":"207-210"},"PeriodicalIF":0.0,"publicationDate":"2003-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67896682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2003-08-31DOI: 10.2174/1568013033483339
J. Geisler
{"title":"Aromatase Inhibitors and Inactivators for the Treatment of Postmenopausal Breast Cancer: A Review","authors":"J. Geisler","doi":"10.2174/1568013033483339","DOIUrl":"https://doi.org/10.2174/1568013033483339","url":null,"abstract":"","PeriodicalId":88234,"journal":{"name":"Current medicinal chemistry. Immunology, endocrine & metabolic agents","volume":"3 1","pages":"261-276"},"PeriodicalIF":0.0,"publicationDate":"2003-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67896768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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