Atmospheric particulatematter(PM)exacerbates the risk factor for Alzheimer’s and Parkinson’s diseases(PD)by promoting the alpha-synuclein(α-syn)pathology in the brain.However,the molecular mechanisms of astrocytes ...Atmospheric particulatematter(PM)exacerbates the risk factor for Alzheimer’s and Parkinson’s diseases(PD)by promoting the alpha-synuclein(α-syn)pathology in the brain.However,the molecular mechanisms of astrocytes involvement inα-syn pathology underlying the process remain unclear.This study investigated PM with particle size<200 nm(PM_(0.2))exposure-inducedα-syn pathology in ICR mice and primary astrocytes,then assessed the effects of mammalian target of rapamycin inhibitor(PP242)in vitro studies.We observed theα-syn pathology in the brains of exposed mice.Meanwhile,PM_(0.2)-exposed mice also exhibited the activation of glial cell and the inhibition of autophagy.In vitro study,PM_(0.2)(3,10 and 30μg/mL)induced inflammatory response and the disorders ofα-syn degradation in primary astrocytes,and lysosomal-associated membrane protein 2(LAMP2)-mediated autophagy underliesα-syn pathology.The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3(LC3II),cathepsin B(CTSB)and lysosomal abundance increased first and then decreased,which might both be a compensatory mechanism to toxicα-syn accumulation induced by PM_(0.2).Moreover,with the transcription factor EB(TFEB)subcellular localization and the increase in LC3II,LAMP2,CTSB,and cathepsin D proteins were identified,leading to the restoration of the degradation ofα-syn after the intervention of PP242.Our results identified that PM_(0.2)exposure could promote theα-syn pathological dysregulation in astrocytes,providing mechanistic insights into how PM_(0.2)increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM_(0.2)toxicity.展开更多
Spinal cord injury （SCI） is one of the most common causes of long-term disability among young adults world-wide. In the United States, 12,000-20,000 new cases are reported annually and approximately half a million p...Spinal cord injury （SCI） is one of the most common causes of long-term disability among young adults world-wide. In the United States, 12,000-20,000 new cases are reported annually and approximately half a million people currently live with SCI. Unfortunately, beyond surgery for immobilization of the spine and prolonged rehabilitation there are no effective treatments to improve functional outcomes after SCI. This is at least in part due to the complex and heterogeneous nature of injury after spinal cord trauma. The physical impact during SCI results in direct mechanical damage to some cells and tissues （primary injury）. Primary injury also sets off a cascade of widespread, progressive biochemical changes leading to further neuronal and glial cell death, neuroinflammation and glial scar formation （secondary injury） （Beattie et al., 2002）.展开更多
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
Autophagy is an evolutionarily well conserved process in which the cellular components including damaged subcellular organelles are engulfed in autophagosome and eventually delivered to lysosome for degradation.It has...Autophagy is an evolutionarily well conserved process in which the cellular components including damaged subcellular organelles are engulfed in autophagosome and eventually delivered to lysosome for degradation.It has been well studied that autophagy is closely implicated in many diseases such as cancer and neurodegenerative diseases.Therefore,the autophagy-lysosome pathway becomes an attractive target in developing novel therapeutic approaches.In the past several years,we have studied the effects of several natural products on the autophagy-lysosome pathway:(i)Andrographolide(Andro),a diterpenoid lactone isolated from an herbal plant Andrographispaniculata,is capable of suppressing autophagy and sensitizing cisplatin-mediated apoptosis in human cancer cells,via blockage of autophagosome-lysosome fusion;(ii)(-)-Epigallocatechin-3-gallate(EGCG),an important green tea polyphenol,induces lysosomal membrane permeabilization(LMP)and eventually leads to lysosome-associated cell death;and(iii)Artesunate(ART),an analog of artemisinin,an anti-malaria drug,is able to kill cancer cells via enhancing lysosomal function and induction of lysosomal degradation of ferritin.Collectively,our findings reveal novel insights into the molecular mechanisms underlying the anti-cancer properties of those natural compounds and demonstrate that targeting the autophagy-lysosome pathway could serve as a new strategy in developing anti-cancer therapeutic agents.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
Alzheimer’s disease(AD),the most common neurodegenerative disorder,is characterized by memory loss and cognitive dysfunction.The accumulation of misfolded protein aggregates including amyloid beta(Aβ)peptides and mi...Alzheimer’s disease(AD),the most common neurodegenerative disorder,is characterized by memory loss and cognitive dysfunction.The accumulation of misfolded protein aggregates including amyloid beta(Aβ)peptides and microtubule associated protein tau(MAPT/tau)in neuronal cells are hallmarks of AD.So far,the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited.Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes.Recently,there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis.Interestingly,the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD.Here,we first summarize the recent genetic,pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD.We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins,Aβand MAPT/tau,in AD.Finally,we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials.Overall,this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.展开更多
Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white...Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white matter(WM)and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion(2VO).The results showed that cognitive impairment occurred by the 28th day after 2VO.Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day.By the 14th day,abnormal accumulation of autophagy substrate,lysosomal dysfunction,and the activation of mechanistic target of rapamycin(MTOR)pathway were observed in WM,paralleled with mature oligodendrocyte death.This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction.To target the ALP dysfunction,enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1(BECN1)in oligodendrocytes reduced mature oligodendrocyte death,and subsequently alleviated the WMI and cognitive impairment after CCH.These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO,which was associated with the aggravation of WMI and cognitive impairment.This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.展开更多
基金supported by the National Science Foundation of China(No.21906100)the Applied Basic Research Project of Shanxi Province(Nos.201901D211333,201901D211327,and 202203021211246).
文摘Atmospheric particulatematter(PM)exacerbates the risk factor for Alzheimer’s and Parkinson’s diseases(PD)by promoting the alpha-synuclein(α-syn)pathology in the brain.However,the molecular mechanisms of astrocytes involvement inα-syn pathology underlying the process remain unclear.This study investigated PM with particle size<200 nm(PM_(0.2))exposure-inducedα-syn pathology in ICR mice and primary astrocytes,then assessed the effects of mammalian target of rapamycin inhibitor(PP242)in vitro studies.We observed theα-syn pathology in the brains of exposed mice.Meanwhile,PM_(0.2)-exposed mice also exhibited the activation of glial cell and the inhibition of autophagy.In vitro study,PM_(0.2)(3,10 and 30μg/mL)induced inflammatory response and the disorders ofα-syn degradation in primary astrocytes,and lysosomal-associated membrane protein 2(LAMP2)-mediated autophagy underliesα-syn pathology.The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3(LC3II),cathepsin B(CTSB)and lysosomal abundance increased first and then decreased,which might both be a compensatory mechanism to toxicα-syn accumulation induced by PM_(0.2).Moreover,with the transcription factor EB(TFEB)subcellular localization and the increase in LC3II,LAMP2,CTSB,and cathepsin D proteins were identified,leading to the restoration of the degradation ofα-syn after the intervention of PP242.Our results identified that PM_(0.2)exposure could promote theα-syn pathological dysregulation in astrocytes,providing mechanistic insights into how PM_(0.2)increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM_(0.2)toxicity.
基金supported by 2014-MSCRFE-0587 from Maryland Stem Cell Research Fund,NIH R03NS087338 and R01NS091128 to MMLNIH R21NR014053 and P30NR014129 to JW
文摘Spinal cord injury （SCI） is one of the most common causes of long-term disability among young adults world-wide. In the United States, 12,000-20,000 new cases are reported annually and approximately half a million people currently live with SCI. Unfortunately, beyond surgery for immobilization of the spine and prolonged rehabilitation there are no effective treatments to improve functional outcomes after SCI. This is at least in part due to the complex and heterogeneous nature of injury after spinal cord trauma. The physical impact during SCI results in direct mechanical damage to some cells and tissues （primary injury）. Primary injury also sets off a cascade of widespread, progressive biochemical changes leading to further neuronal and glial cell death, neuroinflammation and glial scar formation （secondary injury） （Beattie et al., 2002）.
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.
文摘Autophagy is an evolutionarily well conserved process in which the cellular components including damaged subcellular organelles are engulfed in autophagosome and eventually delivered to lysosome for degradation.It has been well studied that autophagy is closely implicated in many diseases such as cancer and neurodegenerative diseases.Therefore,the autophagy-lysosome pathway becomes an attractive target in developing novel therapeutic approaches.In the past several years,we have studied the effects of several natural products on the autophagy-lysosome pathway:(i)Andrographolide(Andro),a diterpenoid lactone isolated from an herbal plant Andrographispaniculata,is capable of suppressing autophagy and sensitizing cisplatin-mediated apoptosis in human cancer cells,via blockage of autophagosome-lysosome fusion;(ii)(-)-Epigallocatechin-3-gallate(EGCG),an important green tea polyphenol,induces lysosomal membrane permeabilization(LMP)and eventually leads to lysosome-associated cell death;and(iii)Artesunate(ART),an analog of artemisinin,an anti-malaria drug,is able to kill cancer cells via enhancing lysosomal function and induction of lysosomal degradation of ferritin.Collectively,our findings reveal novel insights into the molecular mechanisms underlying the anti-cancer properties of those natural compounds and demonstrate that targeting the autophagy-lysosome pathway could serve as a new strategy in developing anti-cancer therapeutic agents.
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.
基金funding supports from the National Natural Science Foundation of China(82003721,82071193,32170774 and 32000673)Shenzhen Science and Technology Innovation Commission(JCYJ20210324114014039,China)+1 种基金China Postdoctoral Science Foundation(2020M683182)Guangdong Basic and Applied Basic Research Foundation(2020A1515110549,China)。
文摘Alzheimer’s disease(AD),the most common neurodegenerative disorder,is characterized by memory loss and cognitive dysfunction.The accumulation of misfolded protein aggregates including amyloid beta(Aβ)peptides and microtubule associated protein tau(MAPT/tau)in neuronal cells are hallmarks of AD.So far,the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited.Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes.Recently,there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis.Interestingly,the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD.Here,we first summarize the recent genetic,pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD.We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins,Aβand MAPT/tau,in AD.Finally,we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials.Overall,this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.
基金the Natural Science Foundation of Liaoning Province(LJKQZ2021031,2022-MS-246,China)to Yueyang Liu。
文摘Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white matter(WM)and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion(2VO).The results showed that cognitive impairment occurred by the 28th day after 2VO.Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day.By the 14th day,abnormal accumulation of autophagy substrate,lysosomal dysfunction,and the activation of mechanistic target of rapamycin(MTOR)pathway were observed in WM,paralleled with mature oligodendrocyte death.This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction.To target the ALP dysfunction,enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1(BECN1)in oligodendrocytes reduced mature oligodendrocyte death,and subsequently alleviated the WMI and cognitive impairment after CCH.These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO,which was associated with the aggravation of WMI and cognitive impairment.This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.
