Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium cha...Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause episodic ataxia, hemiplegic migraine, and seizures. Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter. Methods: We examined our patient population with episodic ataxia and hemiplegic migraine but with no mutation in either CACNA1A or ATP1A2. We looked for mutations in SLC1A3, which encodes the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft. Results: A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls. Expression studies of the mutant EAAT1 showed decreased expression of the protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant EAAT1 decreased the activity of wild-type EAAT1 but not of two other transporters EAAT2 or EAAT3, suggesting that mutant EAAT1 specifically multimerizes with wild-type EAAT1 to exert its dominant negative effect. Conclusion: Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia.展开更多
Alzheimer's disease(AD)is the most common form of dementia worldwide,impairing memory and cognitive functions due to widespread neuronal death.The global incidence of this neurodegenerative disorder is predicted t...Alzheimer's disease(AD)is the most common form of dementia worldwide,impairing memory and cognitive functions due to widespread neuronal death.The global incidence of this neurodegenerative disorder is predicted to increase rapidly in the near future.This growth in prevalence of AD will create a large burden for health systems worldwide.展开更多
帕金森病(parkinson’s disease,PD)是第二大神经退行性疾病,主要发生于中老年人。中脑黑质致密部(substantia nigra pars compacta,SNpc)多巴胺(dopamine,DA)能神经元的变性丢失导致向基底神经节(basal ganglia,BG)纹状体释放的DA大量...帕金森病(parkinson’s disease,PD)是第二大神经退行性疾病,主要发生于中老年人。中脑黑质致密部(substantia nigra pars compacta,SNpc)多巴胺(dopamine,DA)能神经元的变性丢失导致向基底神经节(basal ganglia,BG)纹状体释放的DA大量减少,致使与PD进展有关的纹状体内谷氨酸(glutamate,Glu)能信号过度传导,而纹状体星形胶质细胞上的兴奋性氨基酸转运蛋白(excitatory amino acid transporters,EAATs)可以调节Glu的清除,因此成为治疗PD的一个潜在靶点。运动干预作为PD的一种辅助治疗手段,能够有效缓解PD相关的行为功能障碍,其机制可能是通过调节纹状体星形胶质细胞EAATs表达水平来介导的。该文从纹状体星形胶质细胞EAATs入手,对它在PD神经退行性病变及PD运动防治中的作用等方面的研究进行综述,以期为运动干预缓解PD相关行为功能障碍的神经生物学机制的研究以及靶向干预提供必要的理论依据和新的思路。展开更多
The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arth...The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arthritis,and managing inflammatory cytokine storms.Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma,the exact mechanism by which it enhances functional recovery after spinal cord injury,particularly its effect on astrocytes,remains unclear.To address this gap,we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury.Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury,restored EAAT2 expression,reduced glutamate levels,and alleviated excitatory toxicity.Furthermore,ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α.Additionally,in glutamate-induced excitotoxicity astrocytes,ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3,thereby reducing glutamate-induced neurotoxicity,calcium influx,oxidative stress,and cell apoptosis,and increasing the complexity of dendritic branching.Collectively,these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes,reduces neurotoxicity,and effectively alleviates inflammatory and immune responses after spinal cord injury,thereby promoting functional recovery after spinal cord injury.展开更多
基金This work was supported by grants from National Natural Science Foundation of China ( No. 39825109) and National Key Project of Basic Science Research (No. G1999054007).
文摘Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause episodic ataxia, hemiplegic migraine, and seizures. Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter. Methods: We examined our patient population with episodic ataxia and hemiplegic migraine but with no mutation in either CACNA1A or ATP1A2. We looked for mutations in SLC1A3, which encodes the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft. Results: A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls. Expression studies of the mutant EAAT1 showed decreased expression of the protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant EAAT1 decreased the activity of wild-type EAAT1 but not of two other transporters EAAT2 or EAAT3, suggesting that mutant EAAT1 specifically multimerizes with wild-type EAAT1 to exert its dominant negative effect. Conclusion: Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia.
文摘Alzheimer's disease(AD)is the most common form of dementia worldwide,impairing memory and cognitive functions due to widespread neuronal death.The global incidence of this neurodegenerative disorder is predicted to increase rapidly in the near future.This growth in prevalence of AD will create a large burden for health systems worldwide.
文摘帕金森病(parkinson’s disease,PD)是第二大神经退行性疾病,主要发生于中老年人。中脑黑质致密部(substantia nigra pars compacta,SNpc)多巴胺(dopamine,DA)能神经元的变性丢失导致向基底神经节(basal ganglia,BG)纹状体释放的DA大量减少,致使与PD进展有关的纹状体内谷氨酸(glutamate,Glu)能信号过度传导,而纹状体星形胶质细胞上的兴奋性氨基酸转运蛋白(excitatory amino acid transporters,EAATs)可以调节Glu的清除,因此成为治疗PD的一个潜在靶点。运动干预作为PD的一种辅助治疗手段,能够有效缓解PD相关的行为功能障碍,其机制可能是通过调节纹状体星形胶质细胞EAATs表达水平来介导的。该文从纹状体星形胶质细胞EAATs入手,对它在PD神经退行性病变及PD运动防治中的作用等方面的研究进行综述,以期为运动干预缓解PD相关行为功能障碍的神经生物学机制的研究以及靶向干预提供必要的理论依据和新的思路。
基金supported by the National Natural Science Foundation of China,No.82272484(to XC).
文摘The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arthritis,and managing inflammatory cytokine storms.Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma,the exact mechanism by which it enhances functional recovery after spinal cord injury,particularly its effect on astrocytes,remains unclear.To address this gap,we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury.Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury,restored EAAT2 expression,reduced glutamate levels,and alleviated excitatory toxicity.Furthermore,ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α.Additionally,in glutamate-induced excitotoxicity astrocytes,ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3,thereby reducing glutamate-induced neurotoxicity,calcium influx,oxidative stress,and cell apoptosis,and increasing the complexity of dendritic branching.Collectively,these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes,reduces neurotoxicity,and effectively alleviates inflammatory and immune responses after spinal cord injury,thereby promoting functional recovery after spinal cord injury.
