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
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
Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins.The main reason is that pathogenic prion protein has a strong tendency to aggregate,which easily induces the damage to ...Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins.The main reason is that pathogenic prion protein has a strong tendency to aggregate,which easily induces the damage to the central nervous system.Point mutations in the human prion protein gene can cause prion diseases such as Creutzfeldt-Jakob and Gerstmann's syndrome.To understand the mechanism of mutation-induced prion protein aggregation,the mutants in an aqueous solution are studied by molecular dynamics simulations,including the wild type,V180I,H187R and a double point mutation which is associated with CJD and GSS.After running simulations for 500 ns,the results show that these three mutations have different effects on the kinetic properties of PrP.The high fluctuations around the N-terminal residues of helix 2 in the V180I variant lead to a decrease in hydrogen bonding on helix 2,while an increase in the number of hydrogen bonds between the folded regions promotes the generation ofβ-sheet.Meanwhile,partial deletion of salt bridges in the H187R and double mutants allows the sub-structural domains of the prion protein to separate,which would accelerate the conversion from PrPC to PrPSc.A similar trend is observed in both SASA and Rg for all three mutations,indicating that the conformational space is reduced and the structure is compact.展开更多
Prions are infectious conformations of certain naturally occurring proteins.These misfolded proteins can structurally alter healthy protein,creating misfolded copies that repeat the process and form protein aggr...Prions are infectious conformations of certain naturally occurring proteins.These misfolded proteins can structurally alter healthy protein,creating misfolded copies that repeat the process and form protein aggregates that lead to neuronal cell death.Although years can pass from initial prion infection to clinical presentation of symptoms,onset of symptoms is typically followed by rapid neurological decline resulting in death.Prion diseases have been characterized in animals ranging from sheep and cattle to cervids and humans,with notable cross-species infections such as the variant Creutzfeldt-Jakob disease.Thus,prions present a health risk with the potential to disrupt major food sources as well affect human health through animal to human and human to human transmission events.While human to human prion transmission is rare and the immediate risks for a prion-facilitated pandemic are low,prions are a class of pathogens for which we are underprepared.In addition,prions,and prion disease-like approaches,have also been discussed in the context of biological weapons and toxins,adding another layer of complexity surrounding biosecurity and biodefense.These threats underscore the need for increased scrutiny and research on prions.Here,pharmaceutical and nonpharmaceutical prion-specific interventions are discussed.Recent advances in prion therapeutic development are also briefly highlighted,and a set of policy recommendations are given that aims to provide high level suggestions for the prevention and mitigation of prion diseases.展开更多
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.
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Project supported by the National Natural Science Foundation of China (Grant Nos.52073128,12164002,and 11964012)the Foundation of Educational Committee of Jiangxi Province of China (Grant No.GJJ211112)the Fund for Distinguished Young Scholars of Jiangxi Science&Technology Normal University (Grant No.2015QNBJRC002)。
文摘Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins.The main reason is that pathogenic prion protein has a strong tendency to aggregate,which easily induces the damage to the central nervous system.Point mutations in the human prion protein gene can cause prion diseases such as Creutzfeldt-Jakob and Gerstmann's syndrome.To understand the mechanism of mutation-induced prion protein aggregation,the mutants in an aqueous solution are studied by molecular dynamics simulations,including the wild type,V180I,H187R and a double point mutation which is associated with CJD and GSS.After running simulations for 500 ns,the results show that these three mutations have different effects on the kinetic properties of PrP.The high fluctuations around the N-terminal residues of helix 2 in the V180I variant lead to a decrease in hydrogen bonding on helix 2,while an increase in the number of hydrogen bonds between the folded regions promotes the generation ofβ-sheet.Meanwhile,partial deletion of salt bridges in the H187R and double mutants allows the sub-structural domains of the prion protein to separate,which would accelerate the conversion from PrPC to PrPSc.A similar trend is observed in both SASA and Rg for all three mutations,indicating that the conformational space is reduced and the structure is compact.
文摘Prions are infectious conformations of certain naturally occurring proteins.These misfolded proteins can structurally alter healthy protein,creating misfolded copies that repeat the process and form protein aggregates that lead to neuronal cell death.Although years can pass from initial prion infection to clinical presentation of symptoms,onset of symptoms is typically followed by rapid neurological decline resulting in death.Prion diseases have been characterized in animals ranging from sheep and cattle to cervids and humans,with notable cross-species infections such as the variant Creutzfeldt-Jakob disease.Thus,prions present a health risk with the potential to disrupt major food sources as well affect human health through animal to human and human to human transmission events.While human to human prion transmission is rare and the immediate risks for a prion-facilitated pandemic are low,prions are a class of pathogens for which we are underprepared.In addition,prions,and prion disease-like approaches,have also been discussed in the context of biological weapons and toxins,adding another layer of complexity surrounding biosecurity and biodefense.These threats underscore the need for increased scrutiny and research on prions.Here,pharmaceutical and nonpharmaceutical prion-specific interventions are discussed.Recent advances in prion therapeutic development are also briefly highlighted,and a set of policy recommendations are given that aims to provide high level suggestions for the prevention and mitigation of prion diseases.
