Tau protein (encoded by the MAPT gene) is an attractive therapeutic target for the treatment of Alzheimer’s disease (AD) and other “tauopathies”, where aggregated tau pathology accumulates in neurons. Since tau dep...Tau protein (encoded by the MAPT gene) is an attractive therapeutic target for the treatment of Alzheimer’s disease (AD) and other “tauopathies”, where aggregated tau pathology accumulates in neurons. Since tau deposition is strongly associated with cognitive dysfunction in AD, and tau purportedly mediates the toxicity of β-amyloid, therapies developed to reduce tau or its phosphorylation have been tested preclinically and in several small-scale clinical trials[1]. However, caveats for tau-targeting therapy include the limited understanding of its physiological functions and the complicated interactions between its post-translational modifications, aggregation, and cellular toxicity.展开更多
Ischemic stroke represents a significant danger to human beings,especially the elderly.Interventions are only available to remove the clot,and the mechanism of neuronal death during ischemic stroke is still in debate....Ischemic stroke represents a significant danger to human beings,especially the elderly.Interventions are only available to remove the clot,and the mechanism of neuronal death during ischemic stroke is still in debate.Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs.展开更多
While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanis...While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanism of neurodegeneration in MS has not yet been established. Here, we discovered a potential pathogenetic role of ferroptosis, an iron-dependent regulated cell death mechanism, in MS. We found that critical ferroptosis proteins (acyl-CoA synthetase long-chain family member 4, ACSL4) were altered in an existing genomic database of MS patients, and biochemical features of ferroptosis, including lipid reactive oxygen species (ROS) accumulation and mitochondrial shrinkage, were observed in the experimental autoimmune encephalitis (EAE) mouse model. Targeting ferroptosis with ferroptosis inhibitors or reducing ACSL4 expression improved the behavioral phenotypes of EAE mice, reduced neuroinflammation, and prevented neuronal death. We found that ferroptosis was an early event in EAE, which may promote T-cell activation through T-cell receptor (TCR) signaling in vitro and in vivo. These data indicate that ferroptosis may be a potential target for treating MS.展开更多
Iron deposition in Parkinson’s disease(PD)is a potential disease-modifying target.We previously showed that supplementation of the iron-exporter,ceruloplasmin,selectively corrected nigral iron elevation in the 1-meth...Iron deposition in Parkinson’s disease(PD)is a potential disease-modifying target.We previously showed that supplementation of the iron-exporter,ceruloplasmin,selectively corrected nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)model.Ceruloplasmin delivers iron to transferrin(Tf),the extracellular iron-transporting protein.We show that Tf protein levels are decreased in the nigra of post-mortem PD brains compared with controls(−35%;n=10 each).Because Tf traffics iron away from iron-replete tissues,we hypothesized that Tf supplementation could selectively facilitate iron export from the nigra in PD.In cultured neurons,Tf treatment corrected iron accumulation,and subcutaneous Tf to mice ameliorated iron accumulation and motor deficits in the MPTP model of PD.Although these data support a role for Tf in the disease mechanism for PD,and its potential use for correcting disorders of iron overload,Tf therapy also caused systemic iron depletion,which could limit its application for PD.展开更多
基金supported by the National Clinical Research Center for Geriatrics of West China Hospital (Z2021LC001)the West China Hospital 1.3.5 Project for Disciplines of Excellence(ZYYC20009)。
文摘Tau protein (encoded by the MAPT gene) is an attractive therapeutic target for the treatment of Alzheimer’s disease (AD) and other “tauopathies”, where aggregated tau pathology accumulates in neurons. Since tau deposition is strongly associated with cognitive dysfunction in AD, and tau purportedly mediates the toxicity of β-amyloid, therapies developed to reduce tau or its phosphorylation have been tested preclinically and in several small-scale clinical trials[1]. However, caveats for tau-targeting therapy include the limited understanding of its physiological functions and the complicated interactions between its post-translational modifications, aggregation, and cellular toxicity.
基金This work was supported by the National Key Research and Development Project of China(2018YFC1312300)the National Natural Science Foundation of China(81722016,81801182)+2 种基金he program of National Clinical Research Center for Geriatrics of West China Hospital(Z2021LC001,Z20191001)West China Hospital 1.3.5 project for disciplines of excellence(ZYYC20007,ZYYC20009)Sichuan University postdoctoral interdisciplinary Innovation Fund.
文摘Ischemic stroke represents a significant danger to human beings,especially the elderly.Interventions are only available to remove the clot,and the mechanism of neuronal death during ischemic stroke is still in debate.Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs.
基金the National Natural Science Foundation of China(grant numbers 81773965 to X.H.,81873064 to DO,and 81673664 to QZ).
文摘While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanism of neurodegeneration in MS has not yet been established. Here, we discovered a potential pathogenetic role of ferroptosis, an iron-dependent regulated cell death mechanism, in MS. We found that critical ferroptosis proteins (acyl-CoA synthetase long-chain family member 4, ACSL4) were altered in an existing genomic database of MS patients, and biochemical features of ferroptosis, including lipid reactive oxygen species (ROS) accumulation and mitochondrial shrinkage, were observed in the experimental autoimmune encephalitis (EAE) mouse model. Targeting ferroptosis with ferroptosis inhibitors or reducing ACSL4 expression improved the behavioral phenotypes of EAE mice, reduced neuroinflammation, and prevented neuronal death. We found that ferroptosis was an early event in EAE, which may promote T-cell activation through T-cell receptor (TCR) signaling in vitro and in vivo. These data indicate that ferroptosis may be a potential target for treating MS.
基金This work was supported by funds from the Australian Research Council,the Australian National Health&Medical Research Council(GNT1100441 and GNT1044542)the CRC for Mental Health and Operational Infrastructure Support Victorian State Government。
文摘Iron deposition in Parkinson’s disease(PD)is a potential disease-modifying target.We previously showed that supplementation of the iron-exporter,ceruloplasmin,selectively corrected nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)model.Ceruloplasmin delivers iron to transferrin(Tf),the extracellular iron-transporting protein.We show that Tf protein levels are decreased in the nigra of post-mortem PD brains compared with controls(−35%;n=10 each).Because Tf traffics iron away from iron-replete tissues,we hypothesized that Tf supplementation could selectively facilitate iron export from the nigra in PD.In cultured neurons,Tf treatment corrected iron accumulation,and subcutaneous Tf to mice ameliorated iron accumulation and motor deficits in the MPTP model of PD.Although these data support a role for Tf in the disease mechanism for PD,and its potential use for correcting disorders of iron overload,Tf therapy also caused systemic iron depletion,which could limit its application for PD.
