目的探讨达珀利奈[(E)-Daporinad,FK866]对急性缺血性脑卒中皮层神经炎症、胶质瘢痕增生的影响与机制。方法实验动物分为假手术组(Sham组)、缺血损伤手术组(Vehicle组)和缺血手术后给予FK866干预组(FK866组),每组8只。尼氏染色检测小鼠...目的探讨达珀利奈[(E)-Daporinad,FK866]对急性缺血性脑卒中皮层神经炎症、胶质瘢痕增生的影响与机制。方法实验动物分为假手术组(Sham组)、缺血损伤手术组(Vehicle组)和缺血手术后给予FK866干预组(FK866组),每组8只。尼氏染色检测小鼠大脑皮层缺血损伤程度,TUNEL染色检测神经元凋亡,圆筒试验和网格爬行试验检测小鼠运动、协调能力,免疫组织化学染色检测小鼠大脑皮层缺血部位离子化钙结合适配体分子1(ionized calcium-binding adapter molecule 1,Iba1)与胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)的表达,免疫印迹检测小鼠大脑皮层Iba1、诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)、分化簇206(cluster of differentiation 206,CD206)、GFAP、胶质瘢痕标记物磷酸蛋白聚糖(phosphacan)α和Toll/白细胞介素受体结构域的蛋白1(sterile alpha and TIR motif-containing protein 1,SARM1)的表达。结果与Vehicle组相比,FK866组小鼠大脑皮层缺血灶面积减少,凋亡神经元细胞数量减少,小鼠的运动、协调功能增强,缺血灶部位小胶质细胞及星形胶质细胞的活化减弱,Iba1、iNOS、GFAP和phosphacan蛋白表达水平降低,CD206蛋白水平增高,SARM1的蛋白水平下降。结论在缺血性脑卒中急性期,FK866减轻病灶处的神经元损伤并发挥神经保护作用,可能是通过降低SARM1的表达进而促进小胶质细胞向M2型极化并抑制胶质瘢痕的形成。展开更多
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 ...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.展开更多
Axonal degeneration is one of the key features of neu-rodegenerative disorders.In the canonical view,axonal degeneration destructs neural connections and promotes detrimental disease defects.Here,we assessed the enter...Axonal degeneration is one of the key features of neu-rodegenerative disorders.In the canonical view,axonal degeneration destructs neural connections and promotes detrimental disease defects.Here,we assessed the enteric nervous system(ENS)of the mouse,nonhuman primate,and human by advanced 3D imaging.We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis,and similarly,in mouse colons during acute dextran sulfate sodium-induced colitis.However,we unexpectedly revealed that blockage of such axonal degeneration by the Sarml deletion in mice exacerbated the colitis condition.In contrast,pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation.We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines.Together,this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon,uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.展开更多
无菌α和Toll白介素受体基序蛋白1(sterile alpha and toll interleukin receptor motif-containing protein 1,SARM1)是最新发现的一个在Toll样受体(Toll-like receptor,TLR)通路中起作用的衔接子。SARM1主要在哺乳动物的神经系统中表...无菌α和Toll白介素受体基序蛋白1(sterile alpha and toll interleukin receptor motif-containing protein 1,SARM1)是最新发现的一个在Toll样受体(Toll-like receptor,TLR)通路中起作用的衔接子。SARM1主要在哺乳动物的神经系统中表达,在神经炎症、神经系统的发育中都发挥重要作用。它可以介导神经元的死亡和形态改变,调控神经纤维的瓦勒变性,并且对神经胶质细胞的发生也有影响。与此同时,在面对损伤(感染、外伤、低氧等)时,SARM1作为神经元损伤和先天免疫之间的联系点,为神经退行性疾病和精神疾病等的发病机制研究和治疗方案提供新思路。该文对SARM1在神经系统中作用及机制研究进行综述。展开更多
文摘目的探讨达珀利奈[(E)-Daporinad,FK866]对急性缺血性脑卒中皮层神经炎症、胶质瘢痕增生的影响与机制。方法实验动物分为假手术组(Sham组)、缺血损伤手术组(Vehicle组)和缺血手术后给予FK866干预组(FK866组),每组8只。尼氏染色检测小鼠大脑皮层缺血损伤程度,TUNEL染色检测神经元凋亡,圆筒试验和网格爬行试验检测小鼠运动、协调能力,免疫组织化学染色检测小鼠大脑皮层缺血部位离子化钙结合适配体分子1(ionized calcium-binding adapter molecule 1,Iba1)与胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)的表达,免疫印迹检测小鼠大脑皮层Iba1、诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)、分化簇206(cluster of differentiation 206,CD206)、GFAP、胶质瘢痕标记物磷酸蛋白聚糖(phosphacan)α和Toll/白细胞介素受体结构域的蛋白1(sterile alpha and TIR motif-containing protein 1,SARM1)的表达。结果与Vehicle组相比,FK866组小鼠大脑皮层缺血灶面积减少,凋亡神经元细胞数量减少,小鼠的运动、协调功能增强,缺血灶部位小胶质细胞及星形胶质细胞的活化减弱,Iba1、iNOS、GFAP和phosphacan蛋白表达水平降低,CD206蛋白水平增高,SARM1的蛋白水平下降。结论在缺血性脑卒中急性期,FK866减轻病灶处的神经元损伤并发挥神经保护作用,可能是通过降低SARM1的表达进而促进小胶质细胞向M2型极化并抑制胶质瘢痕的形成。
基金supported by the National Natural Science Foundation of China,No.31972641the National Key Research and Development Program of China,No.2017YFC1200500(both to LFY).
文摘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.
基金This work was funded by the National Key Research and Development Program of China(2019YFA0802003)the National Natural Science Foundation of China(to J.Y.,#31771111,#31970974 and#32061143007)Supports were also provided by Center for Life Sciences,School of Life Sciences,IDG/McGovem Institute for Brain Research,and State Key Laboratory of Membrane Biology at Peking University,by Chinese Institute for Brain Research,and by Institute of Molecular Physiology at The Shenzhen Bay Laboratory.
文摘Axonal degeneration is one of the key features of neu-rodegenerative disorders.In the canonical view,axonal degeneration destructs neural connections and promotes detrimental disease defects.Here,we assessed the enteric nervous system(ENS)of the mouse,nonhuman primate,and human by advanced 3D imaging.We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis,and similarly,in mouse colons during acute dextran sulfate sodium-induced colitis.However,we unexpectedly revealed that blockage of such axonal degeneration by the Sarml deletion in mice exacerbated the colitis condition.In contrast,pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation.We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines.Together,this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon,uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.
文摘无菌α和Toll白介素受体基序蛋白1(sterile alpha and toll interleukin receptor motif-containing protein 1,SARM1)是最新发现的一个在Toll样受体(Toll-like receptor,TLR)通路中起作用的衔接子。SARM1主要在哺乳动物的神经系统中表达,在神经炎症、神经系统的发育中都发挥重要作用。它可以介导神经元的死亡和形态改变,调控神经纤维的瓦勒变性,并且对神经胶质细胞的发生也有影响。与此同时,在面对损伤(感染、外伤、低氧等)时,SARM1作为神经元损伤和先天免疫之间的联系点,为神经退行性疾病和精神疾病等的发病机制研究和治疗方案提供新思路。该文对SARM1在神经系统中作用及机制研究进行综述。
