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Astrocyte in prion disease: a double-edged sword

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Neural Regeneration Research 2022年第8期17卷 1659-1665页

作者： Waqas Tahir Simrika Thapa Hermann M.Schatzl Department of Comparative Biology&Experimental Medicine Faculty of Veterinary MedicineUniversity of CalgaryCalgaryABCanada Calgary prion Research Unit University of CalgaryCalgaryABCanada Hotchkiss Brain Institute University of CalgaryCalgaryABCanada

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 comp

关键词： Alzheimer’s disease astrocytes central nervous system Creutzfeldt-Jakob disease glial cells neurodegeneration prion prion disease prion protein scrapie

SARM1 participates in axonal degeneration and mitochondrial dysfunction in prion disease

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Neural Regeneration Research 2022年第10期17卷 2293-2299页

作者： Meng-Yu Lai Jie Li Xi-Xi Zhang Wei Wu Zhi-Ping Li Zhi-Xin Sun Meng-Yang Zhao Dong-Ming Yang Dong-Dong Wang Wen Li De-Ming Zhao Xiang-Mei Zhou Li-Feng Yang National Animal Transmissible Spongiform Encephalopathy Laboratory College of Veterinary MedicineChina Agricultural UniversityBeijingChina

prion disease represents a group of fatal neurogenerative diseases in humans and animals that are associated with energy loss,axonal degeneration,and mitochondrial dysfunction.Axonal degeneration is an early hallmark of neurodegeneration and is triggered by SARM1.We found that depletion or dysfunctional mutation of SARM1 protected against NAD+loss,axonal degeneration,and mitochondrial functional disorder induced by the neurotoxic peptide PrP106-126.NAD+supplementation rescued prion-triggered axonal degeneration and mitochondrial dysfunction and SARM1 overexpression suppressed this protective effect.NAD+supplementation in PrP106-126-incubated N2a cells,SARM1 depletion,and SARM1 dysfunctional mutation each blocked neuronal apoptosis and increased cell survival.Our results indicate that the axonal degeneration and mitochondrial dysfunction triggered by PrP^(106-126) are partially dependent on SARM1 NADase activity.This pathway has potential as a therapeutic target in the early stages of prion disease.

关键词： axonal degeneration mitochondrial dysfunction NAD+metabolism NADase neurodegenerative disease prion disease SARM1 sterile alpha and TIR motif-containing 1

Epidemiological characteristics of human prion diseases

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Infectious diseases of Poverty 2016年第1期5卷 394-403页

作者： Cao Chen Xiao-Ping Dong State Key Laboratory for Infectious disease Prevention and Control National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionChangbai Rd 155Beijing 102206China Collaborative Innovation Center for Diagnosis and Treatment of Infectious diseases Zhejiang UniversityHangzhou 310003China Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China

Human prion diseases are a group of transmissible,progressive,and invariably fatal neurodegenerative disorders,which include Kuru,Creutzfeldt-Jakob disease(CJD),Gerstmann-Sträussler-Scheinker syndrome,and fatal familial insomnia.Human prion diseases affect approximately 1–2 persons per million worldwide annually,occurring in sporadic,inherited,and acquired forms.These diseases have attracted both scientific and public attention not only because of their mysterious pathogen,but also due to their considerable threat to public health since the emergence of the variant CJD.There are still no specific therapeutic and prophylactic interventions available for prion diseases,thus active surveillance of human prion diseases is critical for disease control and prevention.Since 1993,CJD surveillance systems have been established in many countries and regions,and several long-term multinational cooperative projects have been conducted.In this paper,the epidemiological characteristics of various human prion diseases and the active surveillance systems pertaining to them in different countries and regions are summarized and reviewed.

关键词： prion disease Epidemiology Creutzfeldt-Jakob disease Surveillance

Therapeutic implications of prion diseases

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Biosafety and Health 2021年第2期3卷 92-100页

作者： Cao Chen Xiaoping Dong State Key Laboratory for Infectious disease Prevention and Control NHC Key Laboratory of Medical Virology and Viral DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases(Zhejiang University)National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing 102206China Center for Global Public Health Chinese Center for Disease Control and PreventionBeijing 102206China Chinese Center for disease Control and Prevention- WuhanInstitute of VirologyChinese Academy of Sciences Joint Research Center for Emerging Infectious Diseases and BiosafetyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China China Academy of Chinese Medical Sciences Beijing 100700China

prions are unconventional infectious agents that cause lethal transmissible neurodegenerative diseases in human and animals.prions can be distinguished fromother knownpathogens by their lack of nucleic acids.The most essential process for prion propagation is conversion fromnormal cellular prion protein on the cell membrane to insoluble,limited protease digestion-resistant,pathogenic scrapie prion protein.For dozens of years,many pharmacological tools and interventions targeting different stages of disease progression have been developed and evaluated,and a few have been entered clinical trials.However,no approved prophylactic or therapeutic drugs for prion diseases are available.In this review,we summarize the current concepts in prion research and discuss advances in the research and development of drugs for the prevention and treatment of prion disease.

关键词： prion disease Normal cellular prion protein Pathogenic scrapie prion protein Immunotherapy Natural extracts

Creutzfeldt-Jakob disease presenting as Korsakoff syndrome caused by E196A mutation in PRNP gene:A case report

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世界临床病例杂志 2023年第25期11卷 5982-5987页

作者： Yong-Kang Zhang Jia-Rui Liu Kang-Li Yin Yuan Zong Yu-Zhen Wang Ye-Min Cao Diagnosis and Treatment Center of Vascular disease Shanghai TCM-Integrated HospitalShanghai University of Traditional Chinese MedicineShanghai 200082China

BACKGROUND prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations.In humans,prion diseases result from mutations in the prion protein gene(PRNP).Only a limited number of cases involving a specific PRNP mutation at codon 196(E196A)have been reported.The coexistence of Korsakoff syndrome in patients with Creutzfeldt-Jakob disease(CJD)caused by E196A mutation has not been documented in the existing literature.CASE SUMMARY A 61-year-old Chinese man initially presented with Korsakoff syndrome,followed by rapid-onset dementia,visual hallucinations,akinetic mutism,myoclonus,and hyperthermia.The patient had no significant personal or familial medical history.Magnetic resonance imaging of the brain revealed extensive hyperintense signals in the cortex,while positron emission tomography/computed tomography showed a diffuse reduction in cerebral cortex metabolism.Routine biochemical and microorganism testing of the cerebrospinal fluid(CSF)yielded normal results.Tests for thyroid function,human immunodeficiency virus,syphilis,vitamin B1 and B12 levels,and autoimmune rheumatic disorders were normal.Blood and CSF tests for autoimmune encephalitis and autoantibody-associated paraneoplastic syndrome yielded negative results.A test for 14-3-3 protein in the CSF yielded negative results.Whole-genome sequencing revealed a diseasecausing mutation in PRNP.The patient succumbed to the illness 11 months after the initial symptom onset.CONCLUSION Korsakoff syndrome,typically associated with alcohol intoxication,also manifests in CJD patients.Individuals with CJD along with PRNP E196A mutation may present with Korsakoff syndrome.

关键词： prion disease Creutzfeldt-Jakob disease Korsakoff syndrome PRNP gene 14-3-3 proteins Case report

Recombinant Neural Protein PrP Can Bind with Both Recombinant and Native Apolipoprotein E In Vitro

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Acta Biochimica et Biophysica Sinica 2006年第9期38卷 593-601页

作者： Chen GAO~1 Yan-Jun LEI~(1,2) Jun HAN~1 Qi SHI~1 Lan CHEN~(1,3) Yan GUO~(1,4) Yong-Jun GAO~1 Jian-Ming CHEN~1 Hui-Ying JIANG~1 Wei ZHOU~1 Xiao-Ping DONG~1*1 State Key Laboratory for Infectious disease Prevention and Control,National Institute for Viral disease Control and Prevention,Chinese Center for disease Control and Prevention,Beijing 100052,China 2 School of Medicine,Xi’an Jiaotong University,Xi’an 710061,China 3 National Laboratory of Medical Molecular Biology,Institute of Basic Medical Science,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100005,China 4 College of Science and Veterinary Medicine,Northwest Agriculture and Forest University,Yangling 712100,China State Key Laboratory for Infectious disease Prevention and Control National Institute for Viral Disease Control and Prevention Chinese Center for Disease Control and PreventionBeijing 100052 China School of Medicine Xi'an Jiaotong UniversityXi'an 710061 China National Laboratory of Medical Molecular Biology Institute of Basic Medical Science Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005 China College of Science and Veterinary Medicine Northwest Agriculture and Forest UniversityYangling 712100 China

The most essential and crucial step during the pathogenesis of transmissible spongiformencephalopathy is the conformational change of cellular prion protein （PrPC） to pathologic isoform (PrPSc).Alot of data revealed that caveolae-like domains （CLDs） in the cell surface were the probable place where theconversion of PrP proteins happened.Apolipoprotein E （ApoE） is an apolipoprotein which is considered toplay an important role in the development of Alzheimer’s disease and other neurodegenerative diseases byforming protein complex through binding to the receptor located in the clathrin-coated pits of the cell surface.In this study,a 914-bp cDNA sequence encoding human ApoE3 was amplified from neuroblastoma cell lineSH-SY5Y.Three human ApoE isomers were expressed and purified from Escherichia coli.ApoE-specificantiserum was prepared by immunizing rabbits with the purified ApoE3.GST/His pull-down assay,immunoprecipitation and ELISA revealed that three full-length ApoE isomers interact with the recombinantfull-length PrP protein in vitro.The regions corresponding to protein binding were mapped in the N-terminalsegment of ApoE （amino acid 1-194） and the N-terminal of PrP （amino acid 23-90）.Moreover,the recombinantPrP showed the ability to form a complex with the native ApoE from liver tissues.Our data provided directevidence of molecular interaction between ApoE and PrP.It also supplied scientific clues for assessing thesignificance of CLDs on the surface of cellular membrane in the process of conformational conversion fromPrPC to PrPSc and probing into the pathogenesis of transmissible spongiform encephalopathy.

关键词： prion disease PrP apolipoprotein E protein interaction caveolae-like domain

Preparation of PrP-specific Polyclonal Antibody via Immunization of PRNP-knockout Mice with Recombinant Human PrP Protein

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Biomedical and Environmental Sciences 2020年第7期33卷 493-501页

作者： YANG Xue Hua WU Yue Zhang XIAO Kang GAO Li Ping CHEN Dong Dong DONG Xiao Ping SHI Qi State Key Laboratory for Infectious disease Prevention and Control Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases(Zhejiang University)National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing 102206China Center for Global Public Health Chinese Center for Disease Control and PreventionBeijing 102206China Wuhan Institute of Virology Chinese Academy of ScienceWuhan 430071HubeiChina China Academy of Chinese Medical Sciences Beijing 100700China

Objective The definite diagnosis of human and animal prion diseases depends on the examination of special pathological changes and/or detection of PrPSc in the brain tissues of suspected cases.Thus,developing methods to obtain PrP antibody with good specificity and sensitivity is fundamental for prion identification.Methods We prepared a PrP-specific polyclonal antibody(pAb P54)in a PRNP-knockout mouse model via immunization with recombinant full-length human PrP protein residues 23–231.Thereafter,we verified that pAb in Western blot,immunohistochemistry(IHC),and immunofluorescent(IFA)assays.Results Western blot illustrated that the newly prepared pAb P54 could react with recombinant PrP protein,normal brain PrPC from healthy rodents and humans,and pathological PrPSc in the brains of experimental rodents infected with scrapie and humans infected with different types of prion diseases.The electrophoretic patterns of brain PrPC and PrPSc observed after their reaction with pAb P54 were nearly identical to those produced by commercial PrP monoclonal antibodies.Three glycosylated PrP molecules in the brain homogenates were clearly demonstrated in the reactions of these molecules with pAb P54.IHC assay revealed apparent PrP deposits in the GdnCl-treated brain slices of 139 A-infected mice and 263 K-infected hamsters.IFA tests with pAb P54 also showed clear green signals surrounding blue-stained cell nuclei.Conclusion The newly prepared pAb P54 demonstrated reliable specificity and sensitivity and,thus,may have potential applications not only in studies of prion biology but also in the diagnosis of human and experimental rodent prion diseases.

关键词： prion disease PrP Antibody PRNP-knockout mouse

Remarkable difference of phospholipid molecular chirality in regulating PrP aggregation and cell responses

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中国化学快报：英文版 2023年第2期34卷 236-243页

作者： Cunli Wang Xue Wang Dongdong Wang Shengxu Qian Fusheng Zhang Mingyang Li Minmin Li Wenqi Lu Bo Liu Guangyan Qing School of Biomedical Engineering Dalian University of TechnologyDalian 116024China CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian 116023China College of Chemistry and Chemical Engineering Wuhan Textile UniversityWuhan 430200China

prion diseases are fatal neurodegenerative diseases that can cause severe dementia.The misfolding and accumulation of the prion peptide (PrP)_(106–126) is crucial,and this process is closely relevant to biological membranes.However,how PrP_(106–126)aggregation is affected by the molecular chirality of phospholipid membrane is unknown.Thus,in this study,a pair of L-and D-aspartic acid (Asp)-modified 1,2-dipalmitoyl-sn–glycero-3-phosphoethanolamine (DPPE) were synthesized to construct chiral liposomes.We discover that L-Asp-DPPE liposomes strongly inhibit the oligomerization and amyloidogenesis of PrP_(106–126),whether acting on monomers or oligomers,which rescues cytotoxicity induced by PrP_(106–126).By comparison,D-Asp-DPPE liposomes inhibit peptide oligomerization only at a high concentration and cannot prevent amyloidogenesis when acting on oligomers,which lead to pronounced cytotoxicity.Apoptosis experiment,dynamic change of intracellular Ca^(2+)(_(i)Ca^(2+)) and Ca^(2+)release from endoplasmic reticulum(ER),reactive oxygen species (ROS) production,adsorption dynamics and affinity tests,and fluorescent imaging clearly disclose that molecular chirality of the liposomes dominates conformational transition of PrP_(106–126)from random coil to β-sheet,binding and adsorption of the monomers and oligomers,and subsequent fibrillation process,resulting in distinct inhibition effect in Ca^(2+)overload and release,ROS production and cell apoptosis.This work is the first to report that interfacial molecular chirality is a potentially crucial influence on the fibrillation process of PrP_(106–126) and its cell responses,whereas the convergence of chiral amino acids and liposomes can be considered potential inhibitors in prion diseases.

关键词： prion disease Liposome Chirality Interface Cytosolic Ca^(2+)

Creutzfeldt Jacob’s disease: A Senegalese Observation

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Neuroscience & Medicine 2022年第1期13卷 43-48页

作者： Ahmadou Bamba Mbodji Alassane Mamadou Diop Momo Banda Ndiaye Serigne Saliou Mbacke Khalifa Ababacar Mbaye Rokhaya Diagne Ibrahima Niang Ndiaga Matar Gaye Maouly Fall Adjaratou Sow Anna Basse Lala Bouna Seck Moustapha Ndiaye Amadou Gallo Diop Department of Ibrahima Pierre Ndiaye Neuroscience Fann Hospital Dakar Sénégal Department of Neurology Pikine Hospital Dakar Sénégal Department of Radiology Fann Hospital Dakar Sénégal

Creuzfelt-Jakob disease is a rare and progressive neurodegenerative disease that results in fatal, transmissible, subacute, spongiform encephalopathy characterized by rapidly progressive dementia and movement disorder. We present a 62-year-old male with no medical history who was admitted to our hospital because of gait and balance disturbance, language impairment and progressive motor deficit of the four limbs. A neurological examination found frontal lobe syndrome signs, myoclonic movements, pyramidal and extra-pyramidal signs. Brain Magnetic Resonance Imaging detected high intensity areas in the basal ganglia. EEG showed generalized triphasic sharp-wave complexes. A Cerebro Spinal Fluid examination found protein 14-3-3. Death occurred six months after onset. This is the first known case of Creuzfelt-Jakob disease documented in Senegal.

关键词： Creutzfeldt-Jakob disease Protein 14-3-3 prion disease Rapidly Progressive Dementia