Oxidative stress contributes to the pathogenesis of neurodegenerative diseases.With the aim to find reagents that reduce oxidative stress,a phage display library was screened for peptides mimicking a2,6-sialyllactose(...Oxidative stress contributes to the pathogenesis of neurodegenerative diseases.With the aim to find reagents that reduce oxidative stress,a phage display library was screened for peptides mimicking a2,6-sialyllactose(6'-SL),which is known to beneficially influence neural functions.Using Sambucus nigra lectin,which specifically binds to 6'-SL,we screened a phage display library and found a peptide comprising identical sequences of 12 amino acids.Mimetic peptide,reverse peptide and scrambled peptide were tested for inhibition of 6'-SL binding to the lectin.Indeed,lectin binding to 6'-SL was inhibited by the most frequently identified mimetic peptide,but not by the reverse or scrambled peptides,showing that this peptide mimics 6'-SL.Functionally,mimetic peptide,but not the reverse or scrambled peptides,increased viability and expression of neural cell adhesion molecule L1 in SK-N-SH human neuroblastoma cells,and promoted survival and neurite outgrowth of cultured mouse cerebellar granule neurons challenged by H_20_2-induced oxidative stress.The combined results indicate that the 6'-SL mimetic peptide promotes neuronal survival and neuritogenesis,thus raising hopes for the treatment of neurodegenerative diseases.This study was approved by the Medical Ethics Committee of Shantou University Medical College,China(approval No.SUMC 2014-004)on February 20,2014.展开更多
The canonical Wnt/β-catenin pathway is a highly conserved signaling cascade that plays critical roles during embryogenesis. Wnt ligands regulate axonal extension, growth cone guidance and synaptogenesis throughout th...The canonical Wnt/β-catenin pathway is a highly conserved signaling cascade that plays critical roles during embryogenesis. Wnt ligands regulate axonal extension, growth cone guidance and synaptogenesis throughout the developing central nervous system （CNS）. Recently, studies in mammalian and fish model systems have demonstrated that Wnt/β-catenin signaling also promotes axonal regeneration in the adult optic nerve and spinal cord after injury, raising the possibility that Wnt could be developed as a therapeutic strategy. In this review, we summarize experimental evidence that reveals novel roles for Wnt signaling in the injured CNS, and discuss possible mechanisms by which Wnt ligands could overcome molecular barriers inhibiting axonal growth to promote regeneration. A central challenge in the neuroscience field is developing therapeutic strategies that induce robust axonal regeneration. Although adult axons have the capacity to respond to axonal guidance molecules after injury, there are several major obstacles for axonal growth, including extensive neuronal death, glial scars at the injury site, and lack of axonal guidance signals. Research in rodents demonstrated that activation of Wnt/β-catenin signaling in retinal neurons and radial glia induced neuronal survival and axonal growth, but that activation within reactive glia at the injury site promoted proliferation and glial scar formation. Studies in zebrafish spinal cord injury models confirm an axonal regenerative role for Wnt/β-catenin signaling and identified the cell types responsible. Additionally, in vitro and in vivo studies demonstrated that Wnt induces axonal and neurite growth through transcription-dependent effects of its central mediator β-catenin, potentially by inducing regeneration-promoting genes. Canonical Wnt signaling may also function through transcription-independent interactions of β-catenin with cytoskeletal elements, which could stabilize growing axons and control growth cone movement. Therefore, these studies suggest that Wnt-induced pathways responsible for regulating axonal growth during embryogenesis could be repurposed to promote axonal growth after injury.展开更多
Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopa...Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopamine neurotrophic factor(h CDNF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDNF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDNF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDNF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDNF in dopamine neurons,whose levels remained constant throughout the study in the substantia nigra compacta and striatum.Compared with the lesioned group,tyrosine hydroxylase-positive(TH^(+))nigral cell population and TH+fiber density rose in the substantia nigra compacta and striatum after h CDNF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH^(+)cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved.Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects.These findings support the potential of nanoparticle-mediated h CDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease.The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use(authorization No.162-15)on June 9,2019.展开更多
Following injury, the axons of the mammalian central nervous system do not regenerate. Many studies have aimed at understanding the mechanisms that prevent axonal regeneration and at designing ways to overcome the obs...Following injury, the axons of the mammalian central nervous system do not regenerate. Many studies have aimed at understanding the mechanisms that prevent axonal regeneration and at designing ways to overcome the obstacles preventing axonal regrowth. These studies have identified numerous proteins as promoters of axonal regeneration. In this minireviews, we focus on neuritin as a therapeutic candidate for promoting axonal regeneration. Neuritin was first identified as a neuronal-activity-inducible gene product in the rat brain. The overexpression of neuritin in neurons or the application of neuritin to neurons induces neuritogenesis, neurite arborization, and axonal elongation both in vitro and in vivo. These morphological changes are often observed during the first step of axonal regeneration. Indeed, neuritin expression increases during axonal regeneration in the peripheral nervous system(PNS). Conversely, in a mouse model of diabetes mellitus, neuritin expression decreases in the PNS, and this reduced expression may result in deficient axonal regeneration. Neuritin is induced in the hippocampal dentate gyrus after temporal lobe epilepsy or brain ischemia; however, in these conditions, neuritin induc-tion may exacerbate brain dysfunction through mossy fiber sprouting. Together, these findings support the hypothesis that tightly controlled regulation of neuritin may be required for the treatment of each unique axonal pathology.展开更多
A salient feature of neurons is their intrinsic ability to grow and extend neurites, even in the absence of external cues. Compared to the later stages of neuronal development, such as neuronal polarization and dendri...A salient feature of neurons is their intrinsic ability to grow and extend neurites, even in the absence of external cues. Compared to the later stages of neuronal development, such as neuronal polarization and dendrite morphogenesis, the early steps of neuritogenesis remain relatively unexplored. Here we showed that redistribution of cortical actin into large aggregates preceded neuritoge- nesis and determined the site of neurite initiation. Enhancing actin polymerization by jasplakinolide treat- ment effectively blocked actin redistribution and neurite initiation, while treatment with the actin depolymerizing agents latrunculin A or cytochalasin D accelerated neurite formation. Together, these results demonstrate a critical role of actin dynamics and reorganization in neurite initi- ation. Further experiments showed that microtubule dynamics and protein synthesis are not required for neurite initiation, but are required for later neurite stabilization. The redistribution of actin during early neuronal develop- ment was also observed in the cerebral cortex and hip- pocampus in vivo.展开更多
基金supported by the National Natural Science Foundation of China,No.81471279 and No.81171138(to WJZ)Talent Support Grant from Shantou University Medical College,China,No.2501220118(to WJZ)the Li Kashing Foundation,No.LD030302(to MS)
文摘Oxidative stress contributes to the pathogenesis of neurodegenerative diseases.With the aim to find reagents that reduce oxidative stress,a phage display library was screened for peptides mimicking a2,6-sialyllactose(6'-SL),which is known to beneficially influence neural functions.Using Sambucus nigra lectin,which specifically binds to 6'-SL,we screened a phage display library and found a peptide comprising identical sequences of 12 amino acids.Mimetic peptide,reverse peptide and scrambled peptide were tested for inhibition of 6'-SL binding to the lectin.Indeed,lectin binding to 6'-SL was inhibited by the most frequently identified mimetic peptide,but not by the reverse or scrambled peptides,showing that this peptide mimics 6'-SL.Functionally,mimetic peptide,but not the reverse or scrambled peptides,increased viability and expression of neural cell adhesion molecule L1 in SK-N-SH human neuroblastoma cells,and promoted survival and neurite outgrowth of cultured mouse cerebellar granule neurons challenged by H_20_2-induced oxidative stress.The combined results indicate that the 6'-SL mimetic peptide promotes neuronal survival and neuritogenesis,thus raising hopes for the treatment of neurodegenerative diseases.This study was approved by the Medical Ethics Committee of Shantou University Medical College,China(approval No.SUMC 2014-004)on February 20,2014.
基金provided by the NEI grant R01EY026546AU is a recipient of a Research to Prevent Blindness Medical Student Eye Research Fellowship+2 种基金Financial support from Fight for Sight(summer student fellowship to AU)is gratefully acknowledgedInstitutional support is from an NIH Center Core Grant P30EY014801a Research to Prevent Blindness Unrestricted Grant
文摘The canonical Wnt/β-catenin pathway is a highly conserved signaling cascade that plays critical roles during embryogenesis. Wnt ligands regulate axonal extension, growth cone guidance and synaptogenesis throughout the developing central nervous system （CNS）. Recently, studies in mammalian and fish model systems have demonstrated that Wnt/β-catenin signaling also promotes axonal regeneration in the adult optic nerve and spinal cord after injury, raising the possibility that Wnt could be developed as a therapeutic strategy. In this review, we summarize experimental evidence that reveals novel roles for Wnt signaling in the injured CNS, and discuss possible mechanisms by which Wnt ligands could overcome molecular barriers inhibiting axonal growth to promote regeneration. A central challenge in the neuroscience field is developing therapeutic strategies that induce robust axonal regeneration. Although adult axons have the capacity to respond to axonal guidance molecules after injury, there are several major obstacles for axonal growth, including extensive neuronal death, glial scars at the injury site, and lack of axonal guidance signals. Research in rodents demonstrated that activation of Wnt/β-catenin signaling in retinal neurons and radial glia induced neuronal survival and axonal growth, but that activation within reactive glia at the injury site promoted proliferation and glial scar formation. Studies in zebrafish spinal cord injury models confirm an axonal regenerative role for Wnt/β-catenin signaling and identified the cell types responsible. Additionally, in vitro and in vivo studies demonstrated that Wnt induces axonal and neurite growth through transcription-dependent effects of its central mediator β-catenin, potentially by inducing regeneration-promoting genes. Canonical Wnt signaling may also function through transcription-independent interactions of β-catenin with cytoskeletal elements, which could stabilize growing axons and control growth cone movement. Therefore, these studies suggest that Wnt-induced pathways responsible for regulating axonal growth during embryogenesis could be repurposed to promote axonal growth after injury.
基金supported by the Consejo Nacional de Ciencia Tecnología(Conacyt)de México(Grant#254686,to DMF)。
文摘Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopamine neurotrophic factor(h CDNF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDNF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDNF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDNF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDNF in dopamine neurons,whose levels remained constant throughout the study in the substantia nigra compacta and striatum.Compared with the lesioned group,tyrosine hydroxylase-positive(TH^(+))nigral cell population and TH+fiber density rose in the substantia nigra compacta and striatum after h CDNF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH^(+)cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved.Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects.These findings support the potential of nanoparticle-mediated h CDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease.The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use(authorization No.162-15)on June 9,2019.
基金Supported by JSPS KAKENHI partly,No.24700349,No.24659093,No.25293239MEXT KAKENHI,No.25110737
文摘Following injury, the axons of the mammalian central nervous system do not regenerate. Many studies have aimed at understanding the mechanisms that prevent axonal regeneration and at designing ways to overcome the obstacles preventing axonal regrowth. These studies have identified numerous proteins as promoters of axonal regeneration. In this minireviews, we focus on neuritin as a therapeutic candidate for promoting axonal regeneration. Neuritin was first identified as a neuronal-activity-inducible gene product in the rat brain. The overexpression of neuritin in neurons or the application of neuritin to neurons induces neuritogenesis, neurite arborization, and axonal elongation both in vitro and in vivo. These morphological changes are often observed during the first step of axonal regeneration. Indeed, neuritin expression increases during axonal regeneration in the peripheral nervous system(PNS). Conversely, in a mouse model of diabetes mellitus, neuritin expression decreases in the PNS, and this reduced expression may result in deficient axonal regeneration. Neuritin is induced in the hippocampal dentate gyrus after temporal lobe epilepsy or brain ischemia; however, in these conditions, neuritin induc-tion may exacerbate brain dysfunction through mossy fiber sprouting. Together, these findings support the hypothesis that tightly controlled regulation of neuritin may be required for the treatment of each unique axonal pathology.
基金the ION Optical Imaging Core Facility for technical supportthe IOBS-Nikon Biological Imaging Center for use of the N-SIM microscopesupported by grants from the National Natural Science Foundation of China(31125015 and31321091)
文摘A salient feature of neurons is their intrinsic ability to grow and extend neurites, even in the absence of external cues. Compared to the later stages of neuronal development, such as neuronal polarization and dendrite morphogenesis, the early steps of neuritogenesis remain relatively unexplored. Here we showed that redistribution of cortical actin into large aggregates preceded neuritoge- nesis and determined the site of neurite initiation. Enhancing actin polymerization by jasplakinolide treat- ment effectively blocked actin redistribution and neurite initiation, while treatment with the actin depolymerizing agents latrunculin A or cytochalasin D accelerated neurite formation. Together, these results demonstrate a critical role of actin dynamics and reorganization in neurite initi- ation. Further experiments showed that microtubule dynamics and protein synthesis are not required for neurite initiation, but are required for later neurite stabilization. The redistribution of actin during early neuronal develop- ment was also observed in the cerebral cortex and hip- pocampus in vivo.
