PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different patho...PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.展开更多
BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influen...BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influence of PrPC expression in cholangiocarcinoma(CCA)on patient outcomes following surgical resection.METHODS Patients who underwent curative surgical resection for either intrahepatic or hilar CCA were enrolled in this retrospective study.Based on the immunohistochemical staining results of the surgical specimens,patients were categorized into two groups:The low PrPC group(negative or 1+)and the high PrPC group(2+or 3+).Survival analyses,including overall survival and recurrence-free survival,were conducted using the Kaplan-Meier method and compared using the log-rank test.RESULTS In total,seventy-six patients diagnosed with CCA(39 with intrahepatic and 37 with hilar CCA)underwent curative hepatectomy from January 2011 to November 2021.Among these patients,38(50%)demonstrated high PrPC expression,whereas the remaining 38(50%)showed low expression of PrPC.During a median follow-up period of 31.2 months(range:1 to 137 months),the high PrPC group had a significantly shorter median overall survival than the low PrPC group(40.4 months vs 137.9 months,respectively;P=0.041).Moreover,the high PrPC group had a significantly shorter median recurrence-free survival than the low PrPC group(13.3 months vs 23.8 months,respectively;P=0.026).CONCLUSION PrPC expression is significantly associated with early recurrence and decreased survival period in CCA patients following surgical resection.Thus,PrPC may be used as a prognostic factor in treatment planning.展开更多
Background:Prion diseases(PrDs)are fatal transmissible neurodegenerative disorders caused by misfolded prion protein,which is highly expressed in the brain.Drosophila has been employed as a model system for studying m...Background:Prion diseases(PrDs)are fatal transmissible neurodegenerative disorders caused by misfolded prion protein,which is highly expressed in the brain.Drosophila has been employed as a model system for studying mammalian neurodegenerative diseases.Methods:Drosophila transgenic for hamster prion protein(HaPrP)was generated by Valium20 transformation.Locomotion,longevity,protease resistance,and histology were assessed,and nontargeted metabolomics analyses were performed to investigate the changes in Drosophila metabolism with the HaPrP expression and metformin treatment.Results:The Drosophila model exhibited pan-neuronal expression of HaPrP,with expression levels increasing with age.Flies displayed reduced climbing ability,shortened lifespan,and vacuolar structures in the brain.Additionally,HaPrP expressed in older flies demonstrated resistance to digestion by 5μg/mL Proteinase K.The Drosophila model also displayed alterations in protein,lipid,and carbohydrate metabolism.We hypothesize that glutamate,N-acetylaspartate,ceramide,phosphatidylethanolamine,dihydroxyacetone phosphate,ribose-5-phosphate,and pyruvate are key metabolites potentially related to PrDs.Metformin improved locomotor activity,reduced PrP res formation,and ameliorated mitochondrial dysfunction in flies,which may be associated with alterations in succinate,pyruvate,choline,and sphingomyelin levels.Conclusions:We generated a Drosophila model of PrDs that recapitulates key pathological features observed in mammals.Preliminary applications have demonstrated that the Drosophila model is suitable for PrDs research and the highthroughput screening of potential therapeutic compounds.展开更多
Neuron glia antigen-2(NG2)glia,also known as oligodendrocyte precursor cells(OPCs),are essential for maintaining the normal function and structure of the central nervous system(CNS)due to their supportive role[1].Unde...Neuron glia antigen-2(NG2)glia,also known as oligodendrocyte precursor cells(OPCs),are essential for maintaining the normal function and structure of the central nervous system(CNS)due to their supportive role[1].Under physiological conditions,NG2 glia are involved in myelination by differentiating into oligodendrocytes,which are responsible for forming the myelin sheath around axons[2].In addition,the NG2 glia can directly influence the activity of neuronal circuits by receiving synaptic input from neurons and generating action potentials[3].Under pathological conditions,such as in response to injury or disease,the NG2 glia proliferate and differentiate to replace damaged oligodendrocytes,contributing to the repair and regeneration of myelin[4].展开更多
Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prio...Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prion protein.These diseases can be spontaneous,heritable,anthropogenic/iatrogenic,or in some cases horizontally transmissible,and include such notable TSEs as bovine spongiform encephalopathy(BSE)of cattle and chronic wasting disease(CWD)of cervids.Although they are both unequivocally protein misfolding disorders,they differ markedly in their pathogenesis,transmissibility,and zoonotic potential.While the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal,CWD,which is readily transmitted through various forms of excreta,has rapidly expanded from its original endemic zone to encompass much of North America,along with recently identified foci in Scandinavia.Most importantly,although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products,so far there have been no conclusive reports on the zoonotic transmission of cWD to humans.The underlying basis for these differences-whether host or agent directed-are not well understood,though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion proteins.With the uncontrolled geographic spread of CWD,it is imperative that we improve our understanding of the factors governing prion disease pathogenesis,transmission,and zoonotic potential.展开更多
A conformal structure of a prion protein is thought to cause a prion disease by S.B. Prusiner＇s theory. Knot theory in mathematics is useful in studying a topological difference of topological objects. In this articl...A conformal structure of a prion protein is thought to cause a prion disease by S.B. Prusiner＇s theory. Knot theory in mathematics is useful in studying a topological difference of topological objects. In this article, concerning this conjecture, a topological model of prion proteins （PrPc, PrPsc） called a prion-tangle is introduced to discuss a question of whether or not the prion proteins are easily entangled by an approach from the mathematical knot theory. It is noted that any prion-string with trivial loop which is a topological model of a prion protein can not be entangled topologically unless a certain restriction such as ＂Rotaxsane Property＂ is imposed on it. Nevertheless, it is shown that any two split prion-tangles can be changed by a one-crossing change into a non-split prion-tangle with the given prion-tangles contained while some attentions are paid to the loop systems. The proof is made by a mathematical argument on knot theory of spatial graphs. This means that the question above is answered affirmatively in this topological model of prion-tangles. Next, a question of what is the simplest topological situation of the non-split prion-tangles is considered. By a mathematical argument, it is determined for every n 〉 1 that the minimal crossing number of n-string non-split prion-tangles is 2n or 2n-2, respectively, according to whether or not the assumption that the loop system is a trivial link is counted.展开更多
Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion d...Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc,neuronal loss,spongiform degeneration and astrogliosis in the brain.Prion diseases affect human and animals,there is no effective therapy,and they invariably remain fatal.For a long time,neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis,and the contribution of non-neuronal cells like microglia and astrocytes was considered less important.Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain,but the exact role of these non-neuronal cells during prion pathology is still elusive.Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions.However,astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains.Additionally,sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified,differentially expressed in the brain during prion infection.Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes.Recently,we established a murine astrocyte cell line persistently infected with mouse-adapted prions,and showed how such astrocytes differentially process various prion strains.Considering the complexity of the role of astrocytes in prion pathogenesis,we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes,their differential regulation of signaling cascades,and the interaction with neurons and microglia during prion pathogenesis.This will help to establish novel in vivo models and define new therapeutic targets against prion diseases.In this review,we will discuss the complex role of astrocytes in prion disease,the existing experimental resources,the challenges to analyze the contribution of astrocytes in prion disease pathogenesis,and future strategies to improve the understanding of their role in prion disease.展开更多
Transmissible spongiform encephalopathy or prion disease is triggered by the conversion from cellular prion protein to pathogenic prion protein. Growing evidence has concentrated on prion protein configuration changes...Transmissible spongiform encephalopathy or prion disease is triggered by the conversion from cellular prion protein to pathogenic prion protein. Growing evidence has concentrated on prion protein configuration changes and their correlation with prion disease transmissibility and patho- genicity. In vivo and in vitro studies have shown that several cytosolic forms of prion protein with specific topological structure can destroy intracellular stability and contribute to prion protein pathogenicity. In this study, the latest molecular chaperone system associated with endoplasmic re- ticulum-associated protein degradation, the endoplasmic reticulum resident protein quality-control system and the ubiquitination proteasome system, is outlined. The molecular chaperone system directly correlates with the prion protein degradation pathway. Understanding the molecular mechanisms will help provide a fascinating avenue for further investigations on prion disease treatment and prion protein-induced neurodegenerative diseases.展开更多
基金supported by Telethon Italy award GGP15225(to RC and GM)Italian Ministry of Health award RF-2016-02362950(to RC and CZ)+1 种基金the CJD Foundation USA(to RC)the Associazione Italiana Encefalopatie da Prioni(AIEnP)(to RC).
文摘PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.
基金Supported by National Research Foundation of Korea Grant Funded by the Korea Government,No.RS-2023-00213951.
文摘BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influence of PrPC expression in cholangiocarcinoma(CCA)on patient outcomes following surgical resection.METHODS Patients who underwent curative surgical resection for either intrahepatic or hilar CCA were enrolled in this retrospective study.Based on the immunohistochemical staining results of the surgical specimens,patients were categorized into two groups:The low PrPC group(negative or 1+)and the high PrPC group(2+or 3+).Survival analyses,including overall survival and recurrence-free survival,were conducted using the Kaplan-Meier method and compared using the log-rank test.RESULTS In total,seventy-six patients diagnosed with CCA(39 with intrahepatic and 37 with hilar CCA)underwent curative hepatectomy from January 2011 to November 2021.Among these patients,38(50%)demonstrated high PrPC expression,whereas the remaining 38(50%)showed low expression of PrPC.During a median follow-up period of 31.2 months(range:1 to 137 months),the high PrPC group had a significantly shorter median overall survival than the low PrPC group(40.4 months vs 137.9 months,respectively;P=0.041).Moreover,the high PrPC group had a significantly shorter median recurrence-free survival than the low PrPC group(13.3 months vs 23.8 months,respectively;P=0.026).CONCLUSION PrPC expression is significantly associated with early recurrence and decreased survival period in CCA patients following surgical resection.Thus,PrPC may be used as a prognostic factor in treatment planning.
基金National Key Research and Development Program,Grant/Award Number:2022YFD1800505Hainan Province Science and Technology Special Fund,Grant/Award Number:ZDYF2024XDNY198+1 种基金Beijing Municipal Natural Science Foundation,Grant/Award Number:6232025Natural Science Foundation of China,Grant/Award Number:32272960。
文摘Background:Prion diseases(PrDs)are fatal transmissible neurodegenerative disorders caused by misfolded prion protein,which is highly expressed in the brain.Drosophila has been employed as a model system for studying mammalian neurodegenerative diseases.Methods:Drosophila transgenic for hamster prion protein(HaPrP)was generated by Valium20 transformation.Locomotion,longevity,protease resistance,and histology were assessed,and nontargeted metabolomics analyses were performed to investigate the changes in Drosophila metabolism with the HaPrP expression and metformin treatment.Results:The Drosophila model exhibited pan-neuronal expression of HaPrP,with expression levels increasing with age.Flies displayed reduced climbing ability,shortened lifespan,and vacuolar structures in the brain.Additionally,HaPrP expressed in older flies demonstrated resistance to digestion by 5μg/mL Proteinase K.The Drosophila model also displayed alterations in protein,lipid,and carbohydrate metabolism.We hypothesize that glutamate,N-acetylaspartate,ceramide,phosphatidylethanolamine,dihydroxyacetone phosphate,ribose-5-phosphate,and pyruvate are key metabolites potentially related to PrDs.Metformin improved locomotor activity,reduced PrP res formation,and ameliorated mitochondrial dysfunction in flies,which may be associated with alterations in succinate,pyruvate,choline,and sphingomyelin levels.Conclusions:We generated a Drosophila model of PrDs that recapitulates key pathological features observed in mammals.Preliminary applications have demonstrated that the Drosophila model is suitable for PrDs research and the highthroughput screening of potential therapeutic compounds.
基金supported by the National Natural Science Foundation of China(32300959)a Guangzhou Scientific Research Grant(SL2024A04J00578)the SCNU Young Faculty Development Program(22KJ04).
文摘Neuron glia antigen-2(NG2)glia,also known as oligodendrocyte precursor cells(OPCs),are essential for maintaining the normal function and structure of the central nervous system(CNS)due to their supportive role[1].Under physiological conditions,NG2 glia are involved in myelination by differentiating into oligodendrocytes,which are responsible for forming the myelin sheath around axons[2].In addition,the NG2 glia can directly influence the activity of neuronal circuits by receiving synaptic input from neurons and generating action potentials[3].Under pathological conditions,such as in response to injury or disease,the NG2 glia proliferate and differentiate to replace damaged oligodendrocytes,contributing to the repair and regeneration of myelin[4].
基金funded in part by the Center on Emerging and Zoonotic Infectious Diseases(CEZID)of the National Institutes of General Medical Sciences underaward number P20GM130448.
文摘Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prion protein.These diseases can be spontaneous,heritable,anthropogenic/iatrogenic,or in some cases horizontally transmissible,and include such notable TSEs as bovine spongiform encephalopathy(BSE)of cattle and chronic wasting disease(CWD)of cervids.Although they are both unequivocally protein misfolding disorders,they differ markedly in their pathogenesis,transmissibility,and zoonotic potential.While the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal,CWD,which is readily transmitted through various forms of excreta,has rapidly expanded from its original endemic zone to encompass much of North America,along with recently identified foci in Scandinavia.Most importantly,although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products,so far there have been no conclusive reports on the zoonotic transmission of cWD to humans.The underlying basis for these differences-whether host or agent directed-are not well understood,though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion proteins.With the uncontrolled geographic spread of CWD,it is imperative that we improve our understanding of the factors governing prion disease pathogenesis,transmission,and zoonotic potential.
文摘A conformal structure of a prion protein is thought to cause a prion disease by S.B. Prusiner＇s theory. Knot theory in mathematics is useful in studying a topological difference of topological objects. In this article, concerning this conjecture, a topological model of prion proteins （PrPc, PrPsc） called a prion-tangle is introduced to discuss a question of whether or not the prion proteins are easily entangled by an approach from the mathematical knot theory. It is noted that any prion-string with trivial loop which is a topological model of a prion protein can not be entangled topologically unless a certain restriction such as ＂Rotaxsane Property＂ is imposed on it. Nevertheless, it is shown that any two split prion-tangles can be changed by a one-crossing change into a non-split prion-tangle with the given prion-tangles contained while some attentions are paid to the loop systems. The proof is made by a mathematical argument on knot theory of spatial graphs. This means that the question above is answered affirmatively in this topological model of prion-tangles. Next, a question of what is the simplest topological situation of the non-split prion-tangles is considered. By a mathematical argument, it is determined for every n 〉 1 that the minimal crossing number of n-string non-split prion-tangles is 2n or 2n-2, respectively, according to whether or not the assumption that the loop system is a trivial link is counted.
基金supported by grants from Alberta Innovates/Alberta Prion Research Institute(APRI grants 201600010 and 201900008)(to HMS)ST had received a University of Calgary Eyes High,Killam and Alberta Innovates Health Solution(AIHS)doctoral fellowship.
文摘Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc,neuronal loss,spongiform degeneration and astrogliosis in the brain.Prion diseases affect human and animals,there is no effective therapy,and they invariably remain fatal.For a long time,neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis,and the contribution of non-neuronal cells like microglia and astrocytes was considered less important.Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain,but the exact role of these non-neuronal cells during prion pathology is still elusive.Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions.However,astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains.Additionally,sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified,differentially expressed in the brain during prion infection.Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes.Recently,we established a murine astrocyte cell line persistently infected with mouse-adapted prions,and showed how such astrocytes differentially process various prion strains.Considering the complexity of the role of astrocytes in prion pathogenesis,we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes,their differential regulation of signaling cascades,and the interaction with neurons and microglia during prion pathogenesis.This will help to establish novel in vivo models and define new therapeutic targets against prion diseases.In this review,we will discuss the complex role of astrocytes in prion disease,the existing experimental resources,the challenges to analyze the contribution of astrocytes in prion disease pathogenesis,and future strategies to improve the understanding of their role in prion disease.
基金supported by the National Natural Science Foundation of China,No.31001048
文摘Transmissible spongiform encephalopathy or prion disease is triggered by the conversion from cellular prion protein to pathogenic prion protein. Growing evidence has concentrated on prion protein configuration changes and their correlation with prion disease transmissibility and patho- genicity. In vivo and in vitro studies have shown that several cytosolic forms of prion protein with specific topological structure can destroy intracellular stability and contribute to prion protein pathogenicity. In this study, the latest molecular chaperone system associated with endoplasmic re- ticulum-associated protein degradation, the endoplasmic reticulum resident protein quality-control system and the ubiquitination proteasome system, is outlined. The molecular chaperone system directly correlates with the prion protein degradation pathway. Understanding the molecular mechanisms will help provide a fascinating avenue for further investigations on prion disease treatment and prion protein-induced neurodegenerative diseases.
