Secondary degeneration occurs commonly in the central nervous system after traumatic injuries and following acute and chronic diseases, including glaucoma. A constellation of mechanisms have been shown to be associate...Secondary degeneration occurs commonly in the central nervous system after traumatic injuries and following acute and chronic diseases, including glaucoma. A constellation of mechanisms have been shown to be associated with secondary degeneration including apoptosis, necrosis, autophagy, oxidative stress, excitotoxicity, derangements in ionic homeostasis and calcium influx. Glial cells, such as microglia, astrocytes and oligodendrocytes, have also been demon- strated to take part in the process of secondary injury. Partial optic nerve transection is a useful model which was established about 13 years ago. The merit of this model compared with other optic nerve injury models used for glaucoma study, including complete optic nerve transection model and optic nerve crush model, is the possibility to separate primary degeneration from secondary degeneration in location. Therefore, it provides a good tool for the study of secondary degeneration. This review will focus on the research progress of the mechanisms of secondary degeneration using partial optic nerve transection model.展开更多
目的观察经Wiltse入路联合选择性关节突融合治疗胸腰椎骨折的临床效果及手术节段运动功能的恢复情况。方法回顾性分析我院2011年3月至2018年3月收治的98例胸腰椎压缩性骨折手术患者的临床资料,根据手术不同入路分为Wiltse入路组和后正...目的观察经Wiltse入路联合选择性关节突融合治疗胸腰椎骨折的临床效果及手术节段运动功能的恢复情况。方法回顾性分析我院2011年3月至2018年3月收治的98例胸腰椎压缩性骨折手术患者的临床资料,根据手术不同入路分为Wiltse入路组和后正中入路组,各49例。比较2组患者手术时间、出血量、卧床时间、引流量、手术前后伤椎后凸Cobb角、VAS评分、JOA评分、取出内固定后椎间活动度等指标。结果98例患者获得6~42个月随访,平均15.8个月。Wiltse入路组术中出血量、术后引流量、术后卧床时间均少于后正中入路组,差异具有统计学意义(P<0.05)。2组患者术后VAS、JOA评分较术前明显改善,差异具有统计学意义(P<0.05);除术后2 d Wiltse入路组VAS评分低于后正中入路组外(P<0.05),2组间术后VAS评分、JOA评分差异无统计学意义(P>0.05)。术后1周和术后3个月,2组患者伤椎椎体Cobb角均明显低于术前,差异有统计学意义(P<0.05)。2组患者术后6个月、12个月取出内固定患者未融合节段活动度明显高于术后18个月取出患者,差异有统计学意义(P<0.05)。结论处理胸腰椎骨折时,选择性融合终板损伤节段并适时取出内固定能够保留非融合节段的运动功能,而Wiltse入路较传统后正中入路具有微创优势。展开更多
Inflammatory events occurring in the distal part of an injured peripheral nerve have, nowadays, a great resonance. Investigating the timing of action of the several cytokines in the important stages of Wallerian degen...Inflammatory events occurring in the distal part of an injured peripheral nerve have, nowadays, a great resonance. Investigating the timing of action of the several cytokines in the important stages of Wallerian degeneration helps to understand the regenerative process and design pharmacologic intervention that promotes and expedites recovery. The complex and synergistic action of inflammatory cytokines finally promotes axonal regeneration. Cytokines can be divided into pro- and anti-inflammatory cytokines that upregulate and downregulate, respectively, the production of inflammatory mediators. While pro-inflammatory cytokines are expressed in the first phase of Wallerian degeneration and promote the recruitment of macrophages, anti-inflammatory cytokines are expressed after this recruitment and downregulate the production of all cytokines, thus determining the end of the process. In this review, we describe the major inflammatory cytokines involved in Wallerian degeneration and the early phases of nerve regeneration. In particular, we focus on interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-β, interleukin-10 and transforming growth factor-β.展开更多
背景:骨关节炎发生后,软骨细胞的自噬受到抑制。而自噬是一种维持细胞稳态的重要生理机制,可降解损伤的大分子和细胞器,改善细胞自噬则有可能缓解骨关节炎的发展。目的:探索软骨细胞自噬在骨关节炎中的作用机制及基于软骨细胞自噬治疗...背景:骨关节炎发生后,软骨细胞的自噬受到抑制。而自噬是一种维持细胞稳态的重要生理机制,可降解损伤的大分子和细胞器,改善细胞自噬则有可能缓解骨关节炎的发展。目的:探索软骨细胞自噬在骨关节炎中的作用机制及基于软骨细胞自噬治疗骨关节炎的方法。方法:在PubMed和中国知网、万方数据库,以“骨关节炎,软骨细胞,自噬,治疗,信号通路,中药,miRNA,osteoarthritis,chondrocyte,autophagy,treatment,signaling pathways,traditional Chinese medicine,miRNA”为检索词,检索2001年1月至今收录的有关骨关节炎中软骨细胞自噬作用机制的基础及临床研究。结果与结论:①骨关节炎的发展与软骨细胞自噬变化有关,在软骨退行性病变的初期,软骨细胞中的自噬被激活,保护软骨细胞以应对各种环境变化;而随着软骨退变,软骨细胞无法维持自噬能力,细胞发生损伤甚至死亡;②哺乳动物雷帕霉素靶蛋白、核因子κB、p53等蛋白激酶和信号通路参与了自噬及其相关过程;③雷帕霉素、二氮嗪、白藜芦醇、miRNAs等均能通过上调软骨细胞自噬活性,进而抑制骨关节炎的发展。展开更多
Our previous studies have shown that long noncoding RNA(lncRNA)H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration,and that it promotes the migration of Schwann cells and slows...Our previous studies have shown that long noncoding RNA(lncRNA)H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration,and that it promotes the migration of Schwann cells and slows down the growth of dorsal root ganglion axons.However,the mechanism by which lncRNA H19 regulates neural repair and regeneration after peripheral nerve injury remains unclear.In this study,we established a Sprague-Dawley rat model of sciatic nerve transection injury.We performed in situ hybridization and found that at 4–7 days after sciatic nerve injury,lncRNA H19 was highly expressed.At 14 days before injury,adeno-associated virus was intrathecally injected into the L4–L5 foramina to disrupt or overexpress lncRNA H19.After overexpression of lncRNA H19,the growth of newly formed axons from the sciatic nerve was inhibited,whereas myelination was enhanced.Then,we performed gait analysis and thermal pain analysis to evaluate rat behavior.We found that lncRNA H19 overexpression delayed the recovery of rat behavior function,whereas interfering with lncRNA H19 expression improved functional recovery.Finally,we examined the expression of lncRNA H19 downstream target SEMA6D,and found that after lncRNA H19 overexpression,the SEMA6D protein level was increased.These findings suggest that lncRNA H19 regulates peripheral nerve degeneration and regeneration through activating SEMA6D in injured nerves.This provides a new clue to understand the role of lncRNA H19 in peripheral nerve degeneration and regeneration.展开更多
Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, they often degenerate prior to neuronal death. Understanding the mechanis...Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, they often degenerate prior to neuronal death. Understanding the mechanisms of neurite degeneration has been an intense focus of neurobiology research in the last two decades. As a result, many discoveries have been made in the molecular pathways that lead to neurite degeneration and the cell-cell interactions responsible for the subsequent clearance of neuronal debris. Drosophila melanogaster has served as a prime in vivo model system for identifying and characterizing the key molecular players in neurite degeneration, thanks to its genetic tractability and easy access to its nervous system. The knowledge learned in the fly provided targets and fuel for studies in other model systems that have further enhanced our understanding of neurodegeneration. In this review, we will introduce the experimental systems developed in Drosophila to investigate injuryinduced neurite degeneration, and then discuss the biological pathways that drive degeneration. We will also cover what is known about the mechanisms of how phagocytes recognize and clear degenerating neurites, and how recent findings in this area enhance our understanding of neurodegenerative disease pathology.展开更多
Motor endplates(MEPs) are important sites of information exchange between motor neurons and skeletal muscle, and are distributed in an organized pattern of lamellae in the muscle. Delayed repair of peripheral nerve in...Motor endplates(MEPs) are important sites of information exchange between motor neurons and skeletal muscle, and are distributed in an organized pattern of lamellae in the muscle. Delayed repair of peripheral nerve injury typically results in unsatisfactory functional recovery because of MEP degeneration. In this study, the mouse tibial nerve was transected and repaired with a biodegradable chitin conduit, immediately following or 1 or 3 months after the injury. Fluorescent α-bungarotoxin was injected to label MEPs. Tissue optical clearing combined with light-sheet microscopy revealed that MEPs were distributed in an organized pattern of lamellae in skeletal muscle after delayed repair for 1 and 3 months. However, the total number of MEPs, the number of MEPs per lamellar cluster, and the maturation of single MEPs in gastrocnemius muscle gradually decreased with increasing denervation time. These findings suggest that delayed repair can restore the spatial distribution of MEPs, but it has an adverse effect on the homogeneity of MEPs in the lamellar clusters and the total number of MEPs in the target muscle. The study procedures were approved by the Animal Ethics Committee of the Peking University People's Hospital(approval No. 2019 PHC015) on April 8, 2019.展开更多
Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high...Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.展开更多
Ionizing radiation can cause changes in nervous system function.However,the underlying mechanism remains unclear.In this study,Coenorhabditis elegans(C.elegans)was irradiated with 75 Gy of ^(60)Co whole-body γ radiat...Ionizing radiation can cause changes in nervous system function.However,the underlying mechanism remains unclear.In this study,Coenorhabditis elegans(C.elegans)was irradiated with 75 Gy of ^(60)Co whole-body γ radiation.Behavioral indicators(head thrashes,touch avoidance,and foraging),and the development of dopaminergic neurons related to behavioral function,were evaluated to assess the effects of ionizing radiation on nervous system function in C.elegans.Various behaviors were impaired after whole-body irradiation and degeneration of dopamine neurons was observed.This suggests that 75 Gy of γ radiation is sufficient to induce nervous system dysfunction.The genes nhr-76 and crm-1,which are reported to be related to nervous system function in human and mouse,were screened by transcriptome sequencing and bioinformatics analysis after irradiation or sham irradiation.The expression levels of these two genes were increased after radiation.Next,RNAi technology was used to inhibit the expression of crm-1,a gene whose homologs are associated with motor neuron development in other species.Downregulation of crm-1 expression effectively alleviated the deleterious effects of ionizing radiation on head thrashes and touch avoidance.It was also found that the expression level of crm-1 was regulated by the nuclear receptor gene nhr-76.The results of this study suggest that knocking down the expression level of nhr-76 can reduce the expression level of crm-1,while down-regulating the expression level of crm-1 can alleviate behavioral disorders induced by ionizing radiation.Therefore,inhibition of crm-1 may be of interest as a potential therapeutic target for ionizing radiation-induced neurological dysfunction.展开更多
Dendrites play irreplaceable roles in the nerve conduction pathway and are vulnerable to various insults.Peripheral axotomy of motor neurons results in the retraction of dendritic arbors,and the dendritic arbor can be...Dendrites play irreplaceable roles in the nerve conduction pathway and are vulnerable to various insults.Peripheral axotomy of motor neurons results in the retraction of dendritic arbors,and the dendritic arbor can be re-expanded when reinnervation is allowed.RhoA is a target that regulates the cytoskeleton and promotes neuronal survival and axon regeneration.However,the role of RhoA in dendrite degeneration and regeneration is unknown.In this study,we explored the potential role of RhoA in dendrites.A line of motor neuronal conditional knockout mice was developed by crossbreeding HB9~(Cre+)mice with RhoA~(flox/flox)mice.We established two models for assaying dendrite degeneration and regeneration,in which the brachial plexus was transection or crush injured,respectively.We found that at 28 days after brachial plexus transection,the density,complexity,and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice were slightly decreased compared with that in Cre mice.Dendrites underwent degeneration at 7 and 14 days after brachial plexus transection and recovered at 28–56 days.The density,complexity,and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice recovered compared with results in Cre mice.These findings suggest that RhoA knockout in motor neurons attenuates dendrite degeneration and promotes dendrite regeneration after peripheral nerve injury.展开更多
Wallerian degeneration is a complex biological process that occurs after nerve injury,and involves nerve degeneration and regeneration.Schwann cells play a crucial role in the cellular and molecular events of Walleria...Wallerian degeneration is a complex biological process that occurs after nerve injury,and involves nerve degeneration and regeneration.Schwann cells play a crucial role in the cellular and molecular events of Wallerian degeneration of the peripheral nervous system.However,Wallerian degeneration regulating nerve injury and repair remains largely unknown,especially the early response.We have previously reported some key regulators of Wallerian degeneration after sciatic nerve injury.Baculoviral inhibitor of apoptosis protein repeat-containing protein 3(BIRC3)is an important factor that regulates apoptosis-inhibiting protein.In this study,we established rat models of right sciatic nerve injury.In vitro Schwann cell models were also established and subjected to gene transfection to inhibit and overexpress BIRC3.The data indicated that BIRC3 expression was significantly up-regulated after sciatic nerve injury.Both BIRC3 upregulation and downregulation affected the migration,proliferation and apoptosis of Schwan cells and affected the expression of related factors through activating c-fos and ERK signal pathway.Inhibition of BIRC3 delayed early Wallerian degeneration through inhibiting the apoptosis of Schwann cells after sciatic nerve injury.These findings suggest that BIRC3 plays an important role in peripheral nerve injury repair and regeneration.The study was approved by the Institutional Animal Care and Use Committee of Nantong University,China(approval No.2019-nsfc004)on March 1,2019.展开更多
Clinical disability following trauma or disease to the spinal cord often involves the loss of vital white matter elements including axons and glia.Although excessive Cais an established driver of axonal degeneration,t...Clinical disability following trauma or disease to the spinal cord often involves the loss of vital white matter elements including axons and glia.Although excessive Cais an established driver of axonal degeneration,therapeutically targeting externally sourced Cato date has had limited success in both basic and clinical studies.Contributing factors that may underlie this limited success include the complexity of the many potential sources of Caentry and the discovery that axons also contain substantial amounts of stored Cathat if inappropriately released could contribute to axonal demise.Axonal Castorage is largely accomplished by the axoplasmic reticulum that is part of a continuous network of the endoplasmic reticulum that provides a major sink and source of intracellular Cafrom the tips of dendrites to axonal terminals.This“neuron-within-a-neuron”is positioned to rapidly respond to diverse external and internal stimuli by amplifying cytosolic Calevels and generating short and long distance regenerative Cawaves through Cainduced Carelease.This review provides a glimpse into the molecular machinery that has been implicated in regulating ryanodine receptor mediated Carelease in axons and how dysregulation and/or overstimulation of these internodal axonal signaling nanocomplexes may directly contribute to Ca-dependent axonal demise.Neuronal ryanodine receptors expressed in dendrites,soma,and axonal terminals have been implicated in synaptic transmission and synaptic plasticity,but a physiological role for internodal localized ryanodine receptors remains largely obscure.Plausible physiological roles for internodal ryanodine receptors and such an elaborate internodal binary membrane signaling network in axons will also be discussed.展开更多
After an insult of white matter tracts,e.g.in the spinal cord or optic nerve,axons react in general by the activation of a tightly regulated self-destruction program.This so-called axon degeneration cascade can be tri...After an insult of white matter tracts,e.g.in the spinal cord or optic nerve,axons react in general by the activation of a tightly regulated self-destruction program.This so-called axon degeneration cascade can be triggered by various causes,including injury,toxins,and genetic defects,and is a shared pathway in many different neurological diseases(Coleman and Hoke,2020).Axonal degeneration is thought to be responsible for disease progression and accumulation of disability across many neurological conditions.The hallmark of early axonal injury is the appearance of local spheroid formations along the axon,often referred to as a“pearl-on-string”pattern or axonal beading or swelling.Although this striking shape change has been observed after various types of injury,such as mechanical,chemical,or inflammatory stimuli,we know little about its exact mechanism and its immediate impact on axonal functionality.In this perspective,we would like to contrast the classical calcium-dependent form of axonal degeneration with a recently described form of a calcium-independent mechanism underlying axonal beading.展开更多
基金supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region,China(HKU 776109M)supported by the Fundamental Research Funds for the Central Universities Grant 21609101
文摘Secondary degeneration occurs commonly in the central nervous system after traumatic injuries and following acute and chronic diseases, including glaucoma. A constellation of mechanisms have been shown to be associated with secondary degeneration including apoptosis, necrosis, autophagy, oxidative stress, excitotoxicity, derangements in ionic homeostasis and calcium influx. Glial cells, such as microglia, astrocytes and oligodendrocytes, have also been demon- strated to take part in the process of secondary injury. Partial optic nerve transection is a useful model which was established about 13 years ago. The merit of this model compared with other optic nerve injury models used for glaucoma study, including complete optic nerve transection model and optic nerve crush model, is the possibility to separate primary degeneration from secondary degeneration in location. Therefore, it provides a good tool for the study of secondary degeneration. This review will focus on the research progress of the mechanisms of secondary degeneration using partial optic nerve transection model.
文摘目的观察经Wiltse入路联合选择性关节突融合治疗胸腰椎骨折的临床效果及手术节段运动功能的恢复情况。方法回顾性分析我院2011年3月至2018年3月收治的98例胸腰椎压缩性骨折手术患者的临床资料,根据手术不同入路分为Wiltse入路组和后正中入路组,各49例。比较2组患者手术时间、出血量、卧床时间、引流量、手术前后伤椎后凸Cobb角、VAS评分、JOA评分、取出内固定后椎间活动度等指标。结果98例患者获得6~42个月随访,平均15.8个月。Wiltse入路组术中出血量、术后引流量、术后卧床时间均少于后正中入路组,差异具有统计学意义(P<0.05)。2组患者术后VAS、JOA评分较术前明显改善,差异具有统计学意义(P<0.05);除术后2 d Wiltse入路组VAS评分低于后正中入路组外(P<0.05),2组间术后VAS评分、JOA评分差异无统计学意义(P>0.05)。术后1周和术后3个月,2组患者伤椎椎体Cobb角均明显低于术前,差异有统计学意义(P<0.05)。2组患者术后6个月、12个月取出内固定患者未融合节段活动度明显高于术后18个月取出患者,差异有统计学意义(P<0.05)。结论处理胸腰椎骨折时,选择性融合终板损伤节段并适时取出内固定能够保留非融合节段的运动功能,而Wiltse入路较传统后正中入路具有微创优势。
基金supported by Regione Piemonte founding(RSF-4097-2009)
文摘Inflammatory events occurring in the distal part of an injured peripheral nerve have, nowadays, a great resonance. Investigating the timing of action of the several cytokines in the important stages of Wallerian degeneration helps to understand the regenerative process and design pharmacologic intervention that promotes and expedites recovery. The complex and synergistic action of inflammatory cytokines finally promotes axonal regeneration. Cytokines can be divided into pro- and anti-inflammatory cytokines that upregulate and downregulate, respectively, the production of inflammatory mediators. While pro-inflammatory cytokines are expressed in the first phase of Wallerian degeneration and promote the recruitment of macrophages, anti-inflammatory cytokines are expressed after this recruitment and downregulate the production of all cytokines, thus determining the end of the process. In this review, we describe the major inflammatory cytokines involved in Wallerian degeneration and the early phases of nerve regeneration. In particular, we focus on interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-β, interleukin-10 and transforming growth factor-β.
文摘背景:骨关节炎发生后,软骨细胞的自噬受到抑制。而自噬是一种维持细胞稳态的重要生理机制,可降解损伤的大分子和细胞器,改善细胞自噬则有可能缓解骨关节炎的发展。目的:探索软骨细胞自噬在骨关节炎中的作用机制及基于软骨细胞自噬治疗骨关节炎的方法。方法:在PubMed和中国知网、万方数据库,以“骨关节炎,软骨细胞,自噬,治疗,信号通路,中药,miRNA,osteoarthritis,chondrocyte,autophagy,treatment,signaling pathways,traditional Chinese medicine,miRNA”为检索词,检索2001年1月至今收录的有关骨关节炎中软骨细胞自噬作用机制的基础及临床研究。结果与结论:①骨关节炎的发展与软骨细胞自噬变化有关,在软骨退行性病变的初期,软骨细胞中的自噬被激活,保护软骨细胞以应对各种环境变化;而随着软骨退变,软骨细胞无法维持自噬能力,细胞发生损伤甚至死亡;②哺乳动物雷帕霉素靶蛋白、核因子κB、p53等蛋白激酶和信号通路参与了自噬及其相关过程;③雷帕霉素、二氮嗪、白藜芦醇、miRNAs等均能通过上调软骨细胞自噬活性,进而抑制骨关节炎的发展。
基金supported by the National Natural Science Foundation of China,Nos.31971277(to DBY),31950410551(to DBY)Scientific Research Foundation for Returned Scholars,Ministry of Education of China(to DBY)+2 种基金a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(to DBY)the Postgraduate Research&Practice Innovation Program of Jiangsu Province of China,No.KYCX 19-2050(to JS)Jiangsu College Students’Innovation and Entrepreneurship Training Program,No.202213993005Y(to YY)。
文摘Our previous studies have shown that long noncoding RNA(lncRNA)H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration,and that it promotes the migration of Schwann cells and slows down the growth of dorsal root ganglion axons.However,the mechanism by which lncRNA H19 regulates neural repair and regeneration after peripheral nerve injury remains unclear.In this study,we established a Sprague-Dawley rat model of sciatic nerve transection injury.We performed in situ hybridization and found that at 4–7 days after sciatic nerve injury,lncRNA H19 was highly expressed.At 14 days before injury,adeno-associated virus was intrathecally injected into the L4–L5 foramina to disrupt or overexpress lncRNA H19.After overexpression of lncRNA H19,the growth of newly formed axons from the sciatic nerve was inhibited,whereas myelination was enhanced.Then,we performed gait analysis and thermal pain analysis to evaluate rat behavior.We found that lncRNA H19 overexpression delayed the recovery of rat behavior function,whereas interfering with lncRNA H19 expression improved functional recovery.Finally,we examined the expression of lncRNA H19 downstream target SEMA6D,and found that after lncRNA H19 overexpression,the SEMA6D protein level was increased.These findings suggest that lncRNA H19 regulates peripheral nerve degeneration and regeneration through activating SEMA6D in injured nerves.This provides a new clue to understand the role of lncRNA H19 in peripheral nerve degeneration and regeneration.
基金supported by a Cornell start-up fund and NIH grants (R01NS099125 and R21OD023824) awarded to C.H.
文摘Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, they often degenerate prior to neuronal death. Understanding the mechanisms of neurite degeneration has been an intense focus of neurobiology research in the last two decades. As a result, many discoveries have been made in the molecular pathways that lead to neurite degeneration and the cell-cell interactions responsible for the subsequent clearance of neuronal debris. Drosophila melanogaster has served as a prime in vivo model system for identifying and characterizing the key molecular players in neurite degeneration, thanks to its genetic tractability and easy access to its nervous system. The knowledge learned in the fly provided targets and fuel for studies in other model systems that have further enhanced our understanding of neurodegeneration. In this review, we will introduce the experimental systems developed in Drosophila to investigate injuryinduced neurite degeneration, and then discuss the biological pathways that drive degeneration. We will also cover what is known about the mechanisms of how phagocytes recognize and clear degenerating neurites, and how recent findings in this area enhance our understanding of neurodegenerative disease pathology.
基金supported by the National Natural Science Foundation of China,Nos.82072162(to XFY),81971177the Natural Science Foundation of Beijing of China,No.7192215(to XFY)。
文摘Motor endplates(MEPs) are important sites of information exchange between motor neurons and skeletal muscle, and are distributed in an organized pattern of lamellae in the muscle. Delayed repair of peripheral nerve injury typically results in unsatisfactory functional recovery because of MEP degeneration. In this study, the mouse tibial nerve was transected and repaired with a biodegradable chitin conduit, immediately following or 1 or 3 months after the injury. Fluorescent α-bungarotoxin was injected to label MEPs. Tissue optical clearing combined with light-sheet microscopy revealed that MEPs were distributed in an organized pattern of lamellae in skeletal muscle after delayed repair for 1 and 3 months. However, the total number of MEPs, the number of MEPs per lamellar cluster, and the maturation of single MEPs in gastrocnemius muscle gradually decreased with increasing denervation time. These findings suggest that delayed repair can restore the spatial distribution of MEPs, but it has an adverse effect on the homogeneity of MEPs in the lamellar clusters and the total number of MEPs in the target muscle. The study procedures were approved by the Animal Ethics Committee of the Peking University People's Hospital(approval No. 2019 PHC015) on April 8, 2019.
基金This work was supported by the National Research Foundation of Korea(NRF)grants funded by the Korea government(MSIT,Ministry of Science and ICT)(NRF-2018M3A9E8023853(to JYC)NRF-2018R1C1B6006145(to JYC)NRF-2018R1A2A1A05020292(to BGK)and NRF-2019R1A5A2026045(to JYC and BGK).
文摘Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.
基金supported by the National Natural Science Foundation of China,Nos.82003391(to NC),U1867204(to YT)the Natural Science Research Projects of Colleges and Universities in Jiangsu Province,No.20KJB310007(to NC).
文摘Ionizing radiation can cause changes in nervous system function.However,the underlying mechanism remains unclear.In this study,Coenorhabditis elegans(C.elegans)was irradiated with 75 Gy of ^(60)Co whole-body γ radiation.Behavioral indicators(head thrashes,touch avoidance,and foraging),and the development of dopaminergic neurons related to behavioral function,were evaluated to assess the effects of ionizing radiation on nervous system function in C.elegans.Various behaviors were impaired after whole-body irradiation and degeneration of dopamine neurons was observed.This suggests that 75 Gy of γ radiation is sufficient to induce nervous system dysfunction.The genes nhr-76 and crm-1,which are reported to be related to nervous system function in human and mouse,were screened by transcriptome sequencing and bioinformatics analysis after irradiation or sham irradiation.The expression levels of these two genes were increased after radiation.Next,RNAi technology was used to inhibit the expression of crm-1,a gene whose homologs are associated with motor neuron development in other species.Downregulation of crm-1 expression effectively alleviated the deleterious effects of ionizing radiation on head thrashes and touch avoidance.It was also found that the expression level of crm-1 was regulated by the nuclear receptor gene nhr-76.The results of this study suggest that knocking down the expression level of nhr-76 can reduce the expression level of crm-1,while down-regulating the expression level of crm-1 can alleviate behavioral disorders induced by ionizing radiation.Therefore,inhibition of crm-1 may be of interest as a potential therapeutic target for ionizing radiation-induced neurological dysfunction.
基金the Ministry of Science and Technology China Brain Initiative Grant,No.2022ZD0204701the National Natural Science Foundation of China,Nos.82071386&81870982(all to JG)。
文摘Dendrites play irreplaceable roles in the nerve conduction pathway and are vulnerable to various insults.Peripheral axotomy of motor neurons results in the retraction of dendritic arbors,and the dendritic arbor can be re-expanded when reinnervation is allowed.RhoA is a target that regulates the cytoskeleton and promotes neuronal survival and axon regeneration.However,the role of RhoA in dendrite degeneration and regeneration is unknown.In this study,we explored the potential role of RhoA in dendrites.A line of motor neuronal conditional knockout mice was developed by crossbreeding HB9~(Cre+)mice with RhoA~(flox/flox)mice.We established two models for assaying dendrite degeneration and regeneration,in which the brachial plexus was transection or crush injured,respectively.We found that at 28 days after brachial plexus transection,the density,complexity,and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice were slightly decreased compared with that in Cre mice.Dendrites underwent degeneration at 7 and 14 days after brachial plexus transection and recovered at 28–56 days.The density,complexity,and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice recovered compared with results in Cre mice.These findings suggest that RhoA knockout in motor neurons attenuates dendrite degeneration and promotes dendrite regeneration after peripheral nerve injury.
基金supported by the National Natural Science Foundation of China,Nos.31971277,31950410551Scientific Research Foundation for Returned Scholars+2 种基金Ministry of Education of ChinaPriority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)the Postgraduate Research&Practice Innovation Program of Jiangsu Province of China,No.KYCX 19-2050(all to DBY)。
文摘Wallerian degeneration is a complex biological process that occurs after nerve injury,and involves nerve degeneration and regeneration.Schwann cells play a crucial role in the cellular and molecular events of Wallerian degeneration of the peripheral nervous system.However,Wallerian degeneration regulating nerve injury and repair remains largely unknown,especially the early response.We have previously reported some key regulators of Wallerian degeneration after sciatic nerve injury.Baculoviral inhibitor of apoptosis protein repeat-containing protein 3(BIRC3)is an important factor that regulates apoptosis-inhibiting protein.In this study,we established rat models of right sciatic nerve injury.In vitro Schwann cell models were also established and subjected to gene transfection to inhibit and overexpress BIRC3.The data indicated that BIRC3 expression was significantly up-regulated after sciatic nerve injury.Both BIRC3 upregulation and downregulation affected the migration,proliferation and apoptosis of Schwan cells and affected the expression of related factors through activating c-fos and ERK signal pathway.Inhibition of BIRC3 delayed early Wallerian degeneration through inhibiting the apoptosis of Schwann cells after sciatic nerve injury.These findings suggest that BIRC3 plays an important role in peripheral nerve injury repair and regeneration.The study was approved by the Institutional Animal Care and Use Committee of Nantong University,China(approval No.2019-nsfc004)on March 1,2019.
基金supported by National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01NS092680(to DPS)。
文摘Clinical disability following trauma or disease to the spinal cord often involves the loss of vital white matter elements including axons and glia.Although excessive Cais an established driver of axonal degeneration,therapeutically targeting externally sourced Cato date has had limited success in both basic and clinical studies.Contributing factors that may underlie this limited success include the complexity of the many potential sources of Caentry and the discovery that axons also contain substantial amounts of stored Cathat if inappropriately released could contribute to axonal demise.Axonal Castorage is largely accomplished by the axoplasmic reticulum that is part of a continuous network of the endoplasmic reticulum that provides a major sink and source of intracellular Cafrom the tips of dendrites to axonal terminals.This“neuron-within-a-neuron”is positioned to rapidly respond to diverse external and internal stimuli by amplifying cytosolic Calevels and generating short and long distance regenerative Cawaves through Cainduced Carelease.This review provides a glimpse into the molecular machinery that has been implicated in regulating ryanodine receptor mediated Carelease in axons and how dysregulation and/or overstimulation of these internodal axonal signaling nanocomplexes may directly contribute to Ca-dependent axonal demise.Neuronal ryanodine receptors expressed in dendrites,soma,and axonal terminals have been implicated in synaptic transmission and synaptic plasticity,but a physiological role for internodal localized ryanodine receptors remains largely obscure.Plausible physiological roles for internodal ryanodine receptors and such an elaborate internodal binary membrane signaling network in axons will also be discussed.
文摘After an insult of white matter tracts,e.g.in the spinal cord or optic nerve,axons react in general by the activation of a tightly regulated self-destruction program.This so-called axon degeneration cascade can be triggered by various causes,including injury,toxins,and genetic defects,and is a shared pathway in many different neurological diseases(Coleman and Hoke,2020).Axonal degeneration is thought to be responsible for disease progression and accumulation of disability across many neurological conditions.The hallmark of early axonal injury is the appearance of local spheroid formations along the axon,often referred to as a“pearl-on-string”pattern or axonal beading or swelling.Although this striking shape change has been observed after various types of injury,such as mechanical,chemical,or inflammatory stimuli,we know little about its exact mechanism and its immediate impact on axonal functionality.In this perspective,we would like to contrast the classical calcium-dependent form of axonal degeneration with a recently described form of a calcium-independent mechanism underlying axonal beading.
