Parkinson’s disease(PD),characterized by loss of nigrostriatal dopaminergic neurons,is one of the most predominant neurodegenerative diseases affecting the elderly population worldwide.The concept of stem cell therap...Parkinson’s disease(PD),characterized by loss of nigrostriatal dopaminergic neurons,is one of the most predominant neurodegenerative diseases affecting the elderly population worldwide.The concept of stem cell therapy in managing neurodegenerative diseases has evolved over the years and has recently rapidly progressed.Neural stem cells(NSCs)have a few key features,including selfrenewal,proliferation,and multipotency,which make them a promising agent targeting neurodegeneration.It is generally agreed that challenges for NSC-based therapy are present at every stage of the transplantation process,including preoperative cell preparation and quality control,perioperative procedures,and postoperative graft preservation,adherence,and overall therapy success.In this review,we provided a comprehensive,careful,and critical discussion of experimental and clinical data alongside the pros and cons of NSC-based therapy in PD.Given the state-of-the-art accomplishments of stem cell therapy,gene therapy,and nanotechnology,we shed light on the perspective of complementing the advantages of each process by developing nano-stem cell therapy,which is currently a research hotspot.Although various obstacles and challenges remain,nano-stem cell therapy holds promise to cure PD,however,continuous improvement and development from the stage of laboratory experiments to the clinical application are necessary.展开更多
Inflammatory responses,including glial cell activation and peripheral immune cell infiltration,are involved in the pathogenesis of Parkinson’s disease(PD).These inflammatory responses appear to be closely related to ...Inflammatory responses,including glial cell activation and peripheral immune cell infiltration,are involved in the pathogenesis of Parkinson’s disease(PD).These inflammatory responses appear to be closely related to the release of extracellular vesicles,such as exosomes.However,the relationships among different forms of glial cell activation,synuclein dysregulation,mitochondrial dysfunction,and exosomes are complicated.This review discusses the multiple roles played by exosomes in PD-associated inflammation and concludes that exosomes can transport toxicα-synuclein oligomers to immature neurons and into the extracellular environment,inducing the oligomerization ofα-synuclein in normal neurons.Misfoldedα-synuclein causes microglia and astrocytes to activate and secrete exosomes.Glial cell-derived exosomes participate in communications between glial cells and neurons,triggering anti-stress and anti-inflammatory responses,in addition to axon growth.The production and release of mitochondrial vesicles and exosomes establish a new mechanism for linking mitochondrial dysfunction to systemic inflammation associated with PD.Given the relevance of exosomes as mediators of neuron-glia communication in neuroinflammation and neuropathogenesis,new targeted treatment strategies are currently being developed that use these types of extracellular vesicles as drug carriers.Exosome-mediated inflammation may be a promising target for intervention in PD patients.展开更多
Synucleins belong to a family of small soluble proteins with chaperonic activity implicated in human diseases, but their normal function is not completely understood. Expression of ?, ? and ?-synucleins was analyzed i...Synucleins belong to a family of small soluble proteins with chaperonic activity implicated in human diseases, but their normal function is not completely understood. Expression of ?, ? and ?-synucleins was analyzed in rat and human lens on different stages of development. No significant expression of ?- and ?-synucleins were found, whereas ?-synuclein was expressed in both species only on early stages of lens development. Examination of ?-synuclein upstream region demonstrated the similarity in its organization with promoter regions of crystallins and heat shock protein’s genes. ?-Synuclein upstream region contains motives identical or similar to regulatory cis-elements in their promoters including binding sites for Pax6 and Sox. These results suggest that ?-synuclein plays a role in distinct temporal events in lens development, presumably acting as a specific chaperone.展开更多
For decades,clinicians have developed medications and therapies to alleviate the symptoms of Parkinson’s disease,but no treatment currently can slow or even stop the progression of this localized neurodegeneration.Fo...For decades,clinicians have developed medications and therapies to alleviate the symptoms of Parkinson’s disease,but no treatment currently can slow or even stop the progression of this localized neurodegeneration.Fortunately,sparked by the genetic revolution,stem cell reprogramming research and the advancing capabilities of personalization in medicine enable forward-thinking to unprecedented patient-specific modeling and cell therapies for Parkinson’s disease using induced pluripotent stem cells(iPSCs).In addition to modeling Parkinson’s disease more accurately than chemically-induced animal models,patient-specific stem cell lines can be created,elucidating the effects of genetic susceptibility and sub-populations’differing responses to in vitro treatments.Sourcing cell therapy with iPSC lines provides ethical advantages because these stem cell lines do not require the sacrifice of human zygotes and genetically-specific drug trails can be tested in vitro without lasting damage to patients.In hopes of finally slowing the progression of Parkinson’s disease or re-establishing function,iPSC lines can ultimately be corrected with gene therapy and used as cell sources for neural transplantation for Parkinson’s disease.With relatively localized neural degeneration,similar to spinal column injury,Parkinson’s disease presents a better candidacy for cell therapy when compared to other diffuse degeneration found in Alzheimer’s or Huntington’s Disease.Neurosurgical implantation of pluripotent cells poses the risk of an innate immune response and tumorigenesis.Precautions,therefore,must be taken to ensure cell line quality before transplantation.While cell quality can be quantified using a number of assays,a yielding a high percentage of therapeutically relevant dopaminergic neurons,minimal de novo genetic mutations,and standard chromosomal structure is of the utmost importance.Current techniques focus on iPSCs because they can be matched with donors using human leukocyte antigens,thereby reducing the severity and risk of immune rejection.In August of 2018,researchers in Kyoto,Japan embarked on the first human clinical trial using iPSC cell therapy transplantation for patients with moderate Parkinson’s disease.Transplantation of many cell sources has already proven to reduce Parkinson’s disease symptoms in mouse and primate models.Here we discuss the history and implications for cell therapy for Parkinson’s disease,as well as the necessary safety standards needed for using iPSC transplantation to slow or halt the progression of Parkinson’s disease.展开更多
α-Synuclein causes synaptic pathologies in several neurodegenerative diseases：Parkinson’s disease（PD）is a neurodegenerative disease that impacts the lives of millions of people worldwide.A pathological hallmark o...α-Synuclein causes synaptic pathologies in several neurodegenerative diseases：Parkinson’s disease（PD）is a neurodegenerative disease that impacts the lives of millions of people worldwide.A pathological hallmark of PD,as well as dementia with Lewy bodies（DLB）and several Alzheimer’s disease variants,is the appearanceof intracellular inclusions called Lewy bodies, which contain high levels of aggregated α-synuclein,展开更多
基金Supported by Narodowe Centrum Nauki,No.2021/42/E/NZ7/00246.
文摘Parkinson’s disease(PD),characterized by loss of nigrostriatal dopaminergic neurons,is one of the most predominant neurodegenerative diseases affecting the elderly population worldwide.The concept of stem cell therapy in managing neurodegenerative diseases has evolved over the years and has recently rapidly progressed.Neural stem cells(NSCs)have a few key features,including selfrenewal,proliferation,and multipotency,which make them a promising agent targeting neurodegeneration.It is generally agreed that challenges for NSC-based therapy are present at every stage of the transplantation process,including preoperative cell preparation and quality control,perioperative procedures,and postoperative graft preservation,adherence,and overall therapy success.In this review,we provided a comprehensive,careful,and critical discussion of experimental and clinical data alongside the pros and cons of NSC-based therapy in PD.Given the state-of-the-art accomplishments of stem cell therapy,gene therapy,and nanotechnology,we shed light on the perspective of complementing the advantages of each process by developing nano-stem cell therapy,which is currently a research hotspot.Although various obstacles and challenges remain,nano-stem cell therapy holds promise to cure PD,however,continuous improvement and development from the stage of laboratory experiments to the clinical application are necessary.
基金supported by the National Natural Science Foundation of China,No.81960242(to XLY)Yunnan Applied Basic Research Project of Yunnan Province of China,Nos.2019FE001-048(to XLY),202001AT070001(to XLY),“One Hundred Young and Middle-aged Academic and Technical Backbone”Training Program of Kunming Medical University,No.60118260105(to XLY)Miaozi Project in Science and Technology Innovation Program of Sichuan Province,No.2020JDRC0057(to HYH).
文摘Inflammatory responses,including glial cell activation and peripheral immune cell infiltration,are involved in the pathogenesis of Parkinson’s disease(PD).These inflammatory responses appear to be closely related to the release of extracellular vesicles,such as exosomes.However,the relationships among different forms of glial cell activation,synuclein dysregulation,mitochondrial dysfunction,and exosomes are complicated.This review discusses the multiple roles played by exosomes in PD-associated inflammation and concludes that exosomes can transport toxicα-synuclein oligomers to immature neurons and into the extracellular environment,inducing the oligomerization ofα-synuclein in normal neurons.Misfoldedα-synuclein causes microglia and astrocytes to activate and secrete exosomes.Glial cell-derived exosomes participate in communications between glial cells and neurons,triggering anti-stress and anti-inflammatory responses,in addition to axon growth.The production and release of mitochondrial vesicles and exosomes establish a new mechanism for linking mitochondrial dysfunction to systemic inflammation associated with PD.Given the relevance of exosomes as mediators of neuron-glia communication in neuroinflammation and neuropathogenesis,new targeted treatment strategies are currently being developed that use these types of extracellular vesicles as drug carriers.Exosome-mediated inflammation may be a promising target for intervention in PD patients.
文摘Synucleins belong to a family of small soluble proteins with chaperonic activity implicated in human diseases, but their normal function is not completely understood. Expression of ?, ? and ?-synucleins was analyzed in rat and human lens on different stages of development. No significant expression of ?- and ?-synucleins were found, whereas ?-synuclein was expressed in both species only on early stages of lens development. Examination of ?-synuclein upstream region demonstrated the similarity in its organization with promoter regions of crystallins and heat shock protein’s genes. ?-Synuclein upstream region contains motives identical or similar to regulatory cis-elements in their promoters including binding sites for Pax6 and Sox. These results suggest that ?-synuclein plays a role in distinct temporal events in lens development, presumably acting as a specific chaperone.
文摘For decades,clinicians have developed medications and therapies to alleviate the symptoms of Parkinson’s disease,but no treatment currently can slow or even stop the progression of this localized neurodegeneration.Fortunately,sparked by the genetic revolution,stem cell reprogramming research and the advancing capabilities of personalization in medicine enable forward-thinking to unprecedented patient-specific modeling and cell therapies for Parkinson’s disease using induced pluripotent stem cells(iPSCs).In addition to modeling Parkinson’s disease more accurately than chemically-induced animal models,patient-specific stem cell lines can be created,elucidating the effects of genetic susceptibility and sub-populations’differing responses to in vitro treatments.Sourcing cell therapy with iPSC lines provides ethical advantages because these stem cell lines do not require the sacrifice of human zygotes and genetically-specific drug trails can be tested in vitro without lasting damage to patients.In hopes of finally slowing the progression of Parkinson’s disease or re-establishing function,iPSC lines can ultimately be corrected with gene therapy and used as cell sources for neural transplantation for Parkinson’s disease.With relatively localized neural degeneration,similar to spinal column injury,Parkinson’s disease presents a better candidacy for cell therapy when compared to other diffuse degeneration found in Alzheimer’s or Huntington’s Disease.Neurosurgical implantation of pluripotent cells poses the risk of an innate immune response and tumorigenesis.Precautions,therefore,must be taken to ensure cell line quality before transplantation.While cell quality can be quantified using a number of assays,a yielding a high percentage of therapeutically relevant dopaminergic neurons,minimal de novo genetic mutations,and standard chromosomal structure is of the utmost importance.Current techniques focus on iPSCs because they can be matched with donors using human leukocyte antigens,thereby reducing the severity and risk of immune rejection.In August of 2018,researchers in Kyoto,Japan embarked on the first human clinical trial using iPSC cell therapy transplantation for patients with moderate Parkinson’s disease.Transplantation of many cell sources has already proven to reduce Parkinson’s disease symptoms in mouse and primate models.Here we discuss the history and implications for cell therapy for Parkinson’s disease,as well as the necessary safety standards needed for using iPSC transplantation to slow or halt the progression of Parkinson’s disease.
基金supported by a grant from National Institutes of Health(NINDS/NIA R01NS078165 to JRM)research funds from the Marine Biological Laboratory(to JRM)a research grant from Horizon 2020 Grant No.In Cure EU Joint Programme-JPND(to LB)
文摘α-Synuclein causes synaptic pathologies in several neurodegenerative diseases：Parkinson’s disease（PD）is a neurodegenerative disease that impacts the lives of millions of people worldwide.A pathological hallmark of PD,as well as dementia with Lewy bodies（DLB）and several Alzheimer’s disease variants,is the appearanceof intracellular inclusions called Lewy bodies, which contain high levels of aggregated α-synuclein,
