Although Parkinson＇s disease is the most common neurodegenerative movement disorder, the mechanisms of pathogenesis remain poorly understood. Recent findings have shown that deregulation of the autophagy-lysosome pat...Although Parkinson＇s disease is the most common neurodegenerative movement disorder, the mechanisms of pathogenesis remain poorly understood. Recent findings have shown that deregulation of the autophagy-lysosome pathway is involved in the pathogenesis of Parkinson＇s disease. This review summarizes the most recent findings and discusses the unique role of the autophagy-lysosome pathway in Parkinson＇s disease to highlight the possibility of Parkinson＇s disease treatment strategies that incorporate autophagy-lysosome pathway modulation.展开更多
Tiantai No.1, a Chinese medicine predominantly composed of powdered Rhizoma Gastrodiae, Radix Ginseng, and Ginkgo leaf at a ratio of 2：1：2 and dissolved in pure water, is neuroprotective in animal models of various ...Tiantai No.1, a Chinese medicine predominantly composed of powdered Rhizoma Gastrodiae, Radix Ginseng, and Ginkgo leaf at a ratio of 2：1：2 and dissolved in pure water, is neuroprotective in animal models of various cognitive disorders, but its molecular mechanism remains unclear. We administered Tiantai No.1 intragastrically to senescence-accelerated mouse prone 8（SAMP8） mice（a model of Alzheimer＇s disease） at doses of 50, 100 or 150 mg/kg per day for 8 weeks and evaluated their behavior in the Morris water maze and expression of Alzheimer＇s disease-related proteins in the brain. Tiantai No.1 shortened the escape latency in the water maze training trials, and increased swimming time in the target quadrant during the spatial probe test, indicating that Tiantai No.1 improved learning and memory in SAMP8 mice. Immunohistochemistry revealed that Tiantai No.1 restored the proliferation potential of Ki67-positive cells in the hippocampus. In addition, mice that had received Tiantai No.1 had fewer astrocytes, and less accumulation of amyloid-beta and phosphorylated tau. These results suggest that Tiantai No.1 is neuroprotective in the SAMP8 mouse model of Alzheimer＇s disease and acts by restoring neuronal number and proliferation potential in the hippocampus, decreasing astrocyte infiltration, and reducing the accumulation of amyloid-beta and phosphorylated tau.展开更多
The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SA...The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug development.In this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell model.Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation.Ciclopirox induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower mobility.These condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP expression.Our results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.展开更多
Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obst...Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.展开更多
目的探讨干扰或过表达动力蛋白重链(dynein heavy chain,Dynhc)基因后,帕金森病(Parkinson disease,PD)模型细胞中α-突触核蛋白的自噬溶酶体途径(autophagy-lysosome pathway,ALP)降解机制。方法按实验要求将SH-SY5Y细胞分为对照组、P...目的探讨干扰或过表达动力蛋白重链(dynein heavy chain,Dynhc)基因后,帕金森病(Parkinson disease,PD)模型细胞中α-突触核蛋白的自噬溶酶体途径(autophagy-lysosome pathway,ALP)降解机制。方法按实验要求将SH-SY5Y细胞分为对照组、PD组、Dynhc干扰组、Dynhc过表达组、Dynhc干扰+雷帕霉素组。用Western blot检测细胞中Dynhc、α-突触核蛋白、微管相关蛋白1轻链3(microtubule-associated protein l light chain 3,LC3)、溶酶体相关膜蛋白2(lysosome-associated membrane protein 2,LAMP2)、微管蛋白、动力蛋白激活蛋白p150、驱动蛋白KIF5B的蛋白表达水平;流式细胞仪检测细胞凋亡水平;免疫共聚焦镜观察微管蛋白结构以及LC3与LAMP的共定位情况。采用SPSS 23.0软件进行统计分析,多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验。结果5组细胞α-突触核蛋白、自噬标记蛋白、微管及微管相关蛋白表达均差异有统计学意义(均P<0.001)。PD组Dynhc、α-突触核蛋白、LC3、LAMP2、p150、KIF5B的蛋白表达水平均高于对照组(均P<0.05);Dynhc干扰组Dynhc、LAMP2、微管蛋白、p150的蛋白表达水平均低于PD组(均P<0.05),α-突触核蛋白、LC3、KIF5B的蛋白表达水平均高于PD组(均P<0.05);Dynhc过表达组α-突触核蛋白、LC3、KIF5B的蛋白表达水平均低于PD组(均P<0.05),Dynhc、LAMP2、p150的蛋白表达水平高于PD组(均P<0.05);Dynhc干扰+雷帕霉素组LC3的蛋白表达水平高于Dynhc干扰组(P<0.05),Dynhc、α-突触核蛋白、LAMP2、微管蛋白、p150、KIF5B的蛋白表达水平与Dynhc干扰组比较差异无统计学意义(均P>0.05)。与对照组比,PD组细胞凋亡水平提高[(12.77±1.66)%,(7.64±1.45)%],微管形态不变,自噬体与溶酶体融合较多;与PD组比,Dynhc干扰组细胞凋亡水平[(18.45±1.91)%]提高,微管形态稀疏,自噬体与溶酶体融合较少;与PD组比,Dynhc过表达组细胞凋亡水平[(9.95±1.56)%]降低,微管结构无明显改变,自展开更多
基金sponsored by the National Natural Science Foundation of China, No. 81100941a Grant of Leading Scientist and Innovation Team in the Science and Technology Development Foundation of Jilin Province, No. 20111805a Youth Grant in the Science and Technology Development Foundation of Jilin Province, No. 20090174
文摘Although Parkinson＇s disease is the most common neurodegenerative movement disorder, the mechanisms of pathogenesis remain poorly understood. Recent findings have shown that deregulation of the autophagy-lysosome pathway is involved in the pathogenesis of Parkinson＇s disease. This review summarizes the most recent findings and discusses the unique role of the autophagy-lysosome pathway in Parkinson＇s disease to highlight the possibility of Parkinson＇s disease treatment strategies that incorporate autophagy-lysosome pathway modulation.
基金funded by the National Natural Science Foundation of China,No.81473742the Guangdong Science and Technology Foundation,No.2013B021800101the Shenzhen Major Project of Science and Technology Planning,No.JCYJ20130401115231337
文摘Tiantai No.1, a Chinese medicine predominantly composed of powdered Rhizoma Gastrodiae, Radix Ginseng, and Ginkgo leaf at a ratio of 2：1：2 and dissolved in pure water, is neuroprotective in animal models of various cognitive disorders, but its molecular mechanism remains unclear. We administered Tiantai No.1 intragastrically to senescence-accelerated mouse prone 8（SAMP8） mice（a model of Alzheimer＇s disease） at doses of 50, 100 or 150 mg/kg per day for 8 weeks and evaluated their behavior in the Morris water maze and expression of Alzheimer＇s disease-related proteins in the brain. Tiantai No.1 shortened the escape latency in the water maze training trials, and increased swimming time in the target quadrant during the spatial probe test, indicating that Tiantai No.1 improved learning and memory in SAMP8 mice. Immunohistochemistry revealed that Tiantai No.1 restored the proliferation potential of Ki67-positive cells in the hippocampus. In addition, mice that had received Tiantai No.1 had fewer astrocytes, and less accumulation of amyloid-beta and phosphorylated tau. These results suggest that Tiantai No.1 is neuroprotective in the SAMP8 mouse model of Alzheimer＇s disease and acts by restoring neuronal number and proliferation potential in the hippocampus, decreasing astrocyte infiltration, and reducing the accumulation of amyloid-beta and phosphorylated tau.
基金supported by grants from Shenzhen Science and Technology Program(Grant No.JCYJ20220530163206015,China)National Key Research and Development Program of China(Grant No.2021YFA0910900)+4 种基金Shenzhen Science and Technology Program(Grant No.JCYJ20220818103017036,China)the National Science Fund for Distinguished Young Scholars(Grant No.82025022,China)Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515110033,China)Guangdong Science and Technology Plan Project,construction of high-level biosafety laboratories(Grant No.2021B1212030010,China)Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515110033,China).
文摘The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug development.In this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell model.Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation.Ciclopirox induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower mobility.These condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP expression.Our results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.
基金supported by National Natural Science Foundation of China(Nos.82073780 and 82273868,China)Shanghai Municipal Natural Science Foundation(No.19ZR1406200,China)。
文摘Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.
文摘目的探讨干扰或过表达动力蛋白重链(dynein heavy chain,Dynhc)基因后,帕金森病(Parkinson disease,PD)模型细胞中α-突触核蛋白的自噬溶酶体途径(autophagy-lysosome pathway,ALP)降解机制。方法按实验要求将SH-SY5Y细胞分为对照组、PD组、Dynhc干扰组、Dynhc过表达组、Dynhc干扰+雷帕霉素组。用Western blot检测细胞中Dynhc、α-突触核蛋白、微管相关蛋白1轻链3(microtubule-associated protein l light chain 3,LC3)、溶酶体相关膜蛋白2(lysosome-associated membrane protein 2,LAMP2)、微管蛋白、动力蛋白激活蛋白p150、驱动蛋白KIF5B的蛋白表达水平;流式细胞仪检测细胞凋亡水平;免疫共聚焦镜观察微管蛋白结构以及LC3与LAMP的共定位情况。采用SPSS 23.0软件进行统计分析,多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验。结果5组细胞α-突触核蛋白、自噬标记蛋白、微管及微管相关蛋白表达均差异有统计学意义(均P<0.001)。PD组Dynhc、α-突触核蛋白、LC3、LAMP2、p150、KIF5B的蛋白表达水平均高于对照组(均P<0.05);Dynhc干扰组Dynhc、LAMP2、微管蛋白、p150的蛋白表达水平均低于PD组(均P<0.05),α-突触核蛋白、LC3、KIF5B的蛋白表达水平均高于PD组(均P<0.05);Dynhc过表达组α-突触核蛋白、LC3、KIF5B的蛋白表达水平均低于PD组(均P<0.05),Dynhc、LAMP2、p150的蛋白表达水平高于PD组(均P<0.05);Dynhc干扰+雷帕霉素组LC3的蛋白表达水平高于Dynhc干扰组(P<0.05),Dynhc、α-突触核蛋白、LAMP2、微管蛋白、p150、KIF5B的蛋白表达水平与Dynhc干扰组比较差异无统计学意义(均P>0.05)。与对照组比,PD组细胞凋亡水平提高[(12.77±1.66)%,(7.64±1.45)%],微管形态不变,自噬体与溶酶体融合较多;与PD组比,Dynhc干扰组细胞凋亡水平[(18.45±1.91)%]提高,微管形态稀疏,自噬体与溶酶体融合较少;与PD组比,Dynhc过表达组细胞凋亡水平[(9.95±1.56)%]降低,微管结构无明显改变,自
