Pub Date : 2024-10-24DOI: 10.1016/j.expneurol.2024.115023
Yane Zheng , Huiying Gu , Yuming Kong
Ischemic stroke remains a leading cause of mortality and disability worldwide, driven by complex pathophysiological mechanisms, including excitotoxicity, oxidative stress, apoptosis, and neuroinflammation. PTEN (Phosphatase and tensin homolog deleted on chromosome 10) plays a crucial role in these processes, influencing key signaling pathways such as PI3K/Akt and mTOR. This review aims to explore PTEN's multifaceted functions in ischemic stroke, examining its interactions with non-coding RNAs, involvement in mitophagy and immune suppression, and overall impact on cellular homeostasis. We will investigate various therapeutic strategies targeting PTEN, including synthetic drugs, natural products, and exosome-based therapies enriched with specific miRNAs. Additionally, we will assess the potential of non-pharmaceutical interventions such as electroacupuncture, exercise, transcranial direct current stimulation (tDCS), and therapeutic hypothermia in modulating PTEN activity to enhance cererbroprotection and functional recovery. By elucidating these aspects, this review aims to inspire and motivate the audience in their research and clinical practice, highlighting PTEN as a promising therapeutic target and paving the way for developing effective treatments for ischemic stroke.
{"title":"Targeting PTEN in ischemic stroke: From molecular mechanisms to therapeutic potentials","authors":"Yane Zheng , Huiying Gu , Yuming Kong","doi":"10.1016/j.expneurol.2024.115023","DOIUrl":"10.1016/j.expneurol.2024.115023","url":null,"abstract":"<div><div>Ischemic stroke remains a leading cause of mortality and disability worldwide, driven by complex pathophysiological mechanisms, including excitotoxicity, oxidative stress, apoptosis, and neuroinflammation. PTEN (Phosphatase and tensin homolog deleted on chromosome 10) plays a crucial role in these processes, influencing key signaling pathways such as PI3K/Akt and mTOR. This review aims to explore PTEN's multifaceted functions in ischemic stroke, examining its interactions with non-coding RNAs, involvement in mitophagy and immune suppression, and overall impact on cellular homeostasis. We will investigate various therapeutic strategies targeting PTEN, including synthetic drugs, natural products, and exosome-based therapies enriched with specific miRNAs. Additionally, we will assess the potential of non-pharmaceutical interventions such as electroacupuncture, exercise, transcranial direct current stimulation (tDCS), and therapeutic hypothermia in modulating PTEN activity to enhance cererbroprotection and functional recovery. By elucidating these aspects, this review aims to inspire and motivate the audience in their research and clinical practice, highlighting PTEN as a promising therapeutic target and paving the way for developing effective treatments for ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115023"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.expneurol.2024.115024
Taishi Takeda , Yoon-Ra Her , Jeong-Ki Kim , Narendra N. Jha , Umrao R. Monani
Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8G470R in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.
肌萎缩性脊髓侧索硬化症（ALS）是一种相对常见的致命性瘫痪性运动神经元疾病，目前几乎没有治疗方法。渐冻人症常常与泛素阳性的运动神经元聚集有关，这种病理现象表明蛋白稳态紊乱。事实上，参与蛋白质运输和降解的细胞伴侣往往是家族性 ALS 的病因。脊髓性肌肉萎缩症（SMA）是由运动神经元缺失和肌肉萎缩导致的第二种常见瘫痪病症。虽然脊髓性肌萎缩症现已得到有效治疗，但该病的运动神经元变性机制仍不清楚。为了解决有关 SMA 的机理问题，我们最近发现了一种该病的遗传修饰因子。该因子是组成型表达的细胞伴侣蛋白 Hspa8 的 G470R 变体，它能阻止运动神经元丢失，防止神经末梢神经丝聚集的异常积累，并抑制疾病的发生。Hspa8 因其在自噬中的作用而广为人知。在它的众多客户中，包括与 ALS 相关的超氧化物歧化酶 1（SOD1）蛋白。鉴于 Hspa8 可抑制 SMA 表型，我们测试了 Hspa8G470R 在突变 SOD1 ALS 小鼠模型中的潜在疾病缓解作用。出乎意料的是，表达 G470R 变体的突变 SOD1 小鼠病情加重。小鼠的运动能力下降，肌肉萎缩加剧，寿命进一步缩短。奇怪的是，小鼠脊髓组织中的 SOD1 蛋白却显著减少。我们的研究结果表明，Hspa8 可调节 ALS 表型。然而，G470R变体非但不会减轻疾病，反而会加重病情。
{"title":"A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1G86R mouse model of amyotrophic lateral sclerosis","authors":"Taishi Takeda , Yoon-Ra Her , Jeong-Ki Kim , Narendra N. Jha , Umrao R. Monani","doi":"10.1016/j.expneurol.2024.115024","DOIUrl":"10.1016/j.expneurol.2024.115024","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8<sup>G470R</sup> in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115024"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.expneurol.2024.115025
Sara M. Ricardez Hernandez , Bassil Ahmed , Yaser Al Rawi , F. Javier Llorente Torres , Mona O. Garro Kacher , Catherine L. Smith , Zayd Al Rawi , Jessica Garcia , Nicole L. Nichols , Christian L. Lorson , Monique A. Lorson
Mutations in the Immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene result in two distinct diseases, SMA with Respiratory Distress Type I (SMARD1) and Charcot Marie Tooth Type 2S (CMT2S). To understand the phenotypic and molecular differences between SMARD1 and CMT2S, and the role of IGHMBP2 in disease development, we generated mouse models based on six IGHMBP2 patient mutations. Previously, we reported the development and characterization of Ighmbp2D564N/D564N mice and in this manuscript, we examine two mutations: D565N (D564N in mice) and H924Y (H922Y in mice) in the Ighmbp2H922Y/H922Y and Ighmbp2D564N/H922Y contexts. We found significant differences between these mouse models, providing critical insight into the role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S. Importantly, these studies also demonstrate how disease pathogenesis is significantly altered in the context of Ighmbp2 D564N and H922Y homozygous recessive and compound heterozygous mutations. Notably, there were short-lived and long-lived lifespan cohorts within Ighmbp2D564N/H922Y mice with early (P12/P16) respiratory pathology serving as a key predictor of lifespan. Despite differences in lifespan, motor function deficits initiated early and progressively worsened in all Ighmbp2D564N/H922Y mice. There was decreased limb skeletal muscle fiber area and increased neuromuscular junction (NMJ) denervation in Ighmbp2D564N/H922Y mice. Consistent with CMT2S, Ighmbp2H922Y/H922Y mice did not have altered lifespans nor respiratory pathology. Interestingly, Ighmbp2H922Y/H922Y limb muscle fibers demonstrated an increase in muscle fiber area followed by a reduction while changes in NMJ innervation were minimal even at P180. This is the first study that demonstrates differences associated with IGHMBP2 function within respiration with those within limb motor function. Significant to our understanding of IGHMBP2 function, we demonstrate that there is a direct correlation between disease pathogenesis associated with these IGHMBP2 patient mutations and IGHMBP2 biochemical activity. Importantly, these studies reveal the dynamic differences that are presented when either a single mutant protein is present (IGHMBP2-D564N or IGHMBP2-H922Y) or two mutant proteins are present (IGHMBP2-D564N and IGHMBP2-H922Y) within cells.
{"title":"Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S","authors":"Sara M. Ricardez Hernandez , Bassil Ahmed , Yaser Al Rawi , F. Javier Llorente Torres , Mona O. Garro Kacher , Catherine L. Smith , Zayd Al Rawi , Jessica Garcia , Nicole L. Nichols , Christian L. Lorson , Monique A. Lorson","doi":"10.1016/j.expneurol.2024.115025","DOIUrl":"10.1016/j.expneurol.2024.115025","url":null,"abstract":"<div><div>Mutations in the Immunoglobulin mu DNA binding protein 2 (<em>IGHMBP2</em>) gene result in two distinct diseases, SMA with Respiratory Distress Type I (SMARD1) and Charcot Marie Tooth Type 2S (CMT2S). To understand the phenotypic and molecular differences between SMARD1 and CMT2S, and the role of IGHMBP2 in disease development, we generated mouse models based on six <em>IGHMBP2</em> patient mutations. Previously, we reported the development and characterization of <em>Ighmbp2</em><sup>D564N/D564N</sup> mice and in this manuscript, we examine two mutations: D565N (D564N in mice) and H924Y (H922Y in mice) in the <em>Ighmbp2</em><sup>H922Y/H922Y</sup> and <em>Ighmbp2</em><sup>D564N/H922Y</sup> contexts. We found significant differences between these mouse models, providing critical insight into the role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S. Importantly, these studies also demonstrate how disease pathogenesis is significantly altered in the context of <em>Ighmbp2</em> D564N and H922Y homozygous recessive and compound heterozygous mutations. Notably, there were short-lived and long-lived lifespan cohorts within <em>Ighmbp2</em><sup>D564N/H922Y</sup> mice with early (P12/P16) respiratory pathology serving as a key predictor of lifespan. Despite differences in lifespan, motor function deficits initiated early and progressively worsened in all <em>Ighmbp2</em><sup>D564N/H922Y</sup> mice. There was decreased limb skeletal muscle fiber area and increased neuromuscular junction (NMJ) denervation in <em>Ighmbp2</em><sup>D564N/H922Y</sup> mice. Consistent with CMT2S, <em>Ighmbp2</em><sup>H922Y/H922Y</sup> mice did not have altered lifespans nor respiratory pathology. Interestingly, <em>Ighmbp2</em><sup>H922Y/H922Y</sup> limb muscle fibers demonstrated an increase in muscle fiber area followed by a reduction while changes in NMJ innervation were minimal even at P180. This is the first study that demonstrates differences associated with IGHMBP2 function within respiration with those within limb motor function. Significant to our understanding of IGHMBP2 function, we demonstrate that there is a direct correlation between disease pathogenesis associated with these <em>IGHMBP2</em> patient mutations and IGHMBP2 biochemical activity. Importantly, these studies reveal the dynamic differences that are presented when either a single mutant protein is present (IGHMBP2-D564N or IGHMBP2-H922Y) or two mutant proteins are present (IGHMBP2-D564N and IGHMBP2-H922Y) within cells.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115025"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22DOI: 10.1016/j.expneurol.2024.115022
Di Wang , Xiaohao Zhang , Zhenqian Huang , Yunzi Li , Xinyi Wang , Jia Wang , Ying Zhao , Qiushi Lv , Min Wu , Mingming Zha , Kang Yuan , Wusheng Zhu , Gelin Xu , Yi Xie
Vascular cognitive impairment and dementia (VCID) is mainly caused by chronic cerebral hypoperfusion and subsequent white matter lesions. Noninvasive transcranial magnetic stimulation has been utilized in treating various neurological disorders. However, the function of theta-burst transcranial magnetic stimulation on VCID remains to be defined. We utilized 4-week bilateral carotid artery stenosis model of male mice to mimic VCID. Intermittent theta-burst stimulation (iTBS) or consecutive theta-burst stimulation (cTBS) was administered for 14 consecutive days. Through luxol fast blue staining, electron microscopy and immunofluorescence, we found that iTBS, not cTBS, significantly improved demyelination, axonal damage and β-amyloid deposition, without affecting cerebral blood flow in VCID mice. At cellular levels, iTBS rescued the loss of mature oligodendrocytes, promoted precursor cell differentiation, and inhibited pro-inflammatory activation of astrocytes and microglia. Notably, iTBS attenuated cognitive deterioration in both short-term retention and long-term spatial memory of VCID mice as indicated by serial neurobehavioral tests. To explore the molecular involvement of iTBS, mRNA sequencing was carried out. By real-time PCR and combined RNA fluorescence in situ hybridization with immunofluorescence, iTBS was confirmed to increase Rxrg expression specifically in mature oligodendrocytes. Collectively, iTBS could ameliorate vascular cognitive dysfunction, probably via mitigating white matter lesions and neuroinflammation in the corpus callosum. Rxrg signaling in mature oligodendrocytes, which was increased by iTBS, might be a potential target for VCID treatment.
{"title":"Theta-burst transcranial magnetic stimulation attenuates chronic ischemic demyelination and vascular cognitive impairment in mice","authors":"Di Wang , Xiaohao Zhang , Zhenqian Huang , Yunzi Li , Xinyi Wang , Jia Wang , Ying Zhao , Qiushi Lv , Min Wu , Mingming Zha , Kang Yuan , Wusheng Zhu , Gelin Xu , Yi Xie","doi":"10.1016/j.expneurol.2024.115022","DOIUrl":"10.1016/j.expneurol.2024.115022","url":null,"abstract":"<div><div>Vascular cognitive impairment and dementia (VCID) is mainly caused by chronic cerebral hypoperfusion and subsequent white matter lesions. Noninvasive transcranial magnetic stimulation has been utilized in treating various neurological disorders. However, the function of theta-burst transcranial magnetic stimulation on VCID remains to be defined. We utilized 4-week bilateral carotid artery stenosis model of male mice to mimic VCID. Intermittent theta-burst stimulation (iTBS) or consecutive theta-burst stimulation (cTBS) was administered for 14 consecutive days. Through luxol fast blue staining, electron microscopy and immunofluorescence, we found that iTBS, not cTBS, significantly improved demyelination, axonal damage and β-amyloid deposition, without affecting cerebral blood flow in VCID mice. At cellular levels, iTBS rescued the loss of mature oligodendrocytes, promoted precursor cell differentiation, and inhibited pro-inflammatory activation of astrocytes and microglia. Notably, iTBS attenuated cognitive deterioration in both short-term retention and long-term spatial memory of VCID mice as indicated by serial neurobehavioral tests. To explore the molecular involvement of iTBS, mRNA sequencing was carried out. By real-time PCR and combined RNA fluorescence in situ hybridization with immunofluorescence, iTBS was confirmed to increase <em>Rxrg</em> expression specifically in mature oligodendrocytes. Collectively, iTBS could ameliorate vascular cognitive dysfunction, probably via mitigating white matter lesions and neuroinflammation in the corpus callosum. <em>Rxrg</em> signaling in mature oligodendrocytes, which was increased by iTBS, might be a potential target for VCID treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115022"},"PeriodicalIF":4.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-19DOI: 10.1016/j.expneurol.2024.115004
Yan Jiang , Li-Yun Wang , Yi Liu , Jian-Jian Li , Sheng-Quan Zhang , Xiao-Jun Feng , Chun-Jun Yang , Yun Zhou
Background
Cold atmospheric plasma (CAP) has been shown to improve the recovery of transected peripheral nerves. We determined the protective role of CAP-activated saline (CAP-AS) treatment in the acute and subacute stages of spinal cord injury (SCI) in mice.
Methods
C57BL/6 SCI mice were treated with CAP-AS for 14 days. Injury recovery was assessed weekly for four weeks by conducting motor function tests, including the Basso Mouse Scale (BMS) and footprint test. Transcriptome analysis was conducted on day 14 to elucidate potential mechanisms, which were further validated through immunofluorescence examinations of the injured spinal cord tissues on day 28 and the levels of proinflammatory cytokines produced by macrophages in vitro.
Results
Compared to the SCI group, the CAP-AS-treated groups presented significantly better hindlimb motor function after four weeks. The downregulated (SCI vs. SCI + CAP-AS, with CAP-AS activated for 20 min) differentially expressed genes (DEGs) were enriched in the extracellular region, extracellular matrix (ECM), and ECM-receptor interaction. In contrast, the upregulated DEGs were enriched in immune response-associated pathways. Histological changes in the CAP-AS-treated groups were observed to further validate the predicted mechanisms 28 days post-injury. The alleviation of secondary injury was confirmed by an increase in GFAP-positive and NFH-positive areas, and enhanced outgrowth of 5-HT-positive fibers. Inhibited ECM remodeling was confirmed by a decrease in the areas positive for PDGFRβ, fibronectin, and laminin. A decrease in the infiltration of macrophages and activation of microglia was determined by a decrease in CD68-positive and F4/80-positive areas. The inhibitory effect of CAP-AS on inflammation was further supported by a decrease in the levels of the proinflammatory cytokines IL-1β, IL-6, and TNF-α in CAP-AS-treated M1 macrophages.
Conclusion
CAP-AS can alleviate secondary injury in SCI model mice by inhibiting ECM remodeling in injured tissues and reducing the infiltration or activation of proinflammatory macrophages/microglia.
{"title":"Cold atmospheric plasma-activated saline alleviates secondary injury post-SCI by inhibiting extracellular matrix remodeling and infiltration of proinflammatory macrophages","authors":"Yan Jiang , Li-Yun Wang , Yi Liu , Jian-Jian Li , Sheng-Quan Zhang , Xiao-Jun Feng , Chun-Jun Yang , Yun Zhou","doi":"10.1016/j.expneurol.2024.115004","DOIUrl":"10.1016/j.expneurol.2024.115004","url":null,"abstract":"<div><h3>Background</h3><div>Cold atmospheric plasma (CAP) has been shown to improve the recovery of transected peripheral nerves. We determined the protective role of CAP-activated saline (CAP-AS) treatment in the acute and subacute stages of spinal cord injury (SCI) in mice.</div></div><div><h3>Methods</h3><div>C57BL/6 SCI mice were treated with CAP-AS for 14 days. Injury recovery was assessed weekly for four weeks by conducting motor function tests, including the Basso Mouse Scale (BMS) and footprint test. Transcriptome analysis was conducted on day 14 to elucidate potential mechanisms, which were further validated through immunofluorescence examinations of the injured spinal cord tissues on day 28 and the levels of proinflammatory cytokines produced by macrophages in vitro.</div></div><div><h3>Results</h3><div>Compared to the SCI group, the CAP-AS-treated groups presented significantly better hindlimb motor function after four weeks. The downregulated (SCI vs. SCI + CAP-AS, with CAP-AS activated for 20 min) differentially expressed genes (DEGs) were enriched in the extracellular region, extracellular matrix (ECM), and ECM-receptor interaction. In contrast, the upregulated DEGs were enriched in immune response-associated pathways. Histological changes in the CAP-AS-treated groups were observed to further validate the predicted mechanisms 28 days post-injury. The alleviation of secondary injury was confirmed by an increase in GFAP-positive and NFH-positive areas, and enhanced outgrowth of 5-HT-positive fibers. Inhibited ECM remodeling was confirmed by a decrease in the areas positive for PDGFRβ, fibronectin, and laminin. A decrease in the infiltration of macrophages and activation of microglia was determined by a decrease in CD68-positive and F4/80-positive areas. The inhibitory effect of CAP-AS on inflammation was further supported by a decrease in the levels of the proinflammatory cytokines IL-1β, IL-6, and TNF-α in CAP-AS-treated M1 macrophages.</div></div><div><h3>Conclusion</h3><div>CAP-AS can alleviate secondary injury in SCI model mice by inhibiting ECM remodeling in injured tissues and reducing the infiltration or activation of proinflammatory macrophages/microglia.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115004"},"PeriodicalIF":4.6,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.expneurol.2024.115007
Xianfei Yang , Ruoling Zheng , Hongyao Zhang , Zixian Ou , Sha Wan , Dongfeng Lin , Jianguo Yan , Mingyue Jin , Jie Tan
Optineurin (OPTN) is an autophagy receptor that participates in the degradation of damaged mitochondria, protein aggregates, and invading pathogens. OPTN is closely related to various types of neurodegenerative diseases. However, the role of OPTN in the central nervous system is unclear. Here, we found that OPTN dysregulation in the compact part of substantia nigra (SNc) led to motor and learning deficits in animal models. Knockdown of OPTN increased total and phosphorylated α-synuclein levels which induced microglial activation and dopaminergic neuronal loss in the SNc. Overexpression of OPTN can't reverse the motor and learning phenotypes. Mechanistic analysis revealed that upregulation of OPTN increased α-synuclein phosphorylation independent of its autophagy receptor activity, which further resulted in microglial activation and dopaminergic neuronal loss similar to OPTN downregulation. Our study uncovers the crucial role of OPTN in maintaining dopaminergic neuron survival and motor and learning functions which are disrupted in PD patients.
{"title":"Optineurin regulates motor and learning behaviors by affecting dopaminergic neuron survival in mice","authors":"Xianfei Yang , Ruoling Zheng , Hongyao Zhang , Zixian Ou , Sha Wan , Dongfeng Lin , Jianguo Yan , Mingyue Jin , Jie Tan","doi":"10.1016/j.expneurol.2024.115007","DOIUrl":"10.1016/j.expneurol.2024.115007","url":null,"abstract":"<div><div>Optineurin (OPTN) is an autophagy receptor that participates in the degradation of damaged mitochondria, protein aggregates, and invading pathogens. OPTN is closely related to various types of neurodegenerative diseases. However, the role of OPTN in the central nervous system is unclear. Here, we found that OPTN dysregulation in the compact part of substantia nigra (SNc) led to motor and learning deficits in animal models. Knockdown of OPTN increased total and phosphorylated α-synuclein levels which induced microglial activation and dopaminergic neuronal loss in the SNc. Overexpression of OPTN can't reverse the motor and learning phenotypes. Mechanistic analysis revealed that upregulation of OPTN increased α-synuclein phosphorylation independent of its autophagy receptor activity, which further resulted in microglial activation and dopaminergic neuronal loss similar to OPTN downregulation. Our study uncovers the crucial role of OPTN in maintaining dopaminergic neuron survival and motor and learning functions which are disrupted in PD patients.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115007"},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.expneurol.2024.115020
Qiuhong Jiang , Ge Li , Huacheng Wang , Weineng Chen , Fengyin Liang , Haifan Kong , Tara S.R. Chen , Lishan Lin , Hua Hong , Zhong Pei
Cognitive impairment is often found at the acute stages and sequelae of coronavirus disease 2019 (COVID-19), and the underlying mechanisms remain unclear. The S1 protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be a cause of cognitive impairment associated with COVID-19. The nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome and neuroinflammation play important roles in Alzheimer's disease (AD) with cognitive impairment. However, their roles remain unknown in COVID-19 with cognitive impairment. We stimulated BV2 cells with S1 protein in vitro and injected the hippocampi of wild-type (WT) mice, NLRP3 knockout (KO), and microglia NLRP3 KO mice in vivo with S1 protein to induce cognitive impairment. We assessed exploratory behavior as associative memory using novel object recognition and Morris water maze tests. Neuroinflammation was analyzed using immunofluorescence and western blotting to detect inflammatory markers. Co-localized NLRP3 and S1 proteins were investigated using confocal microscopy. We found that S1 protein injection led to cognitive impairment, neuronal loss, and neuroinflammation by activating NLRP3 inflammation, and this was reduced by global NLRP3 KO and microglia NLRP3 KO. Furthermore, TAK 242, a specific inhibitor of Toll-like receptor-4, resulted in a significant reduction in NLRP3 and pro-IL-1β in BV2 cells with S1 protein stimulation. These results reveal a distinct mechanism through which the SARS-CoV-2 spike S1 protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.
{"title":"SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent neuroinflammation and cognitive impairment in mice","authors":"Qiuhong Jiang , Ge Li , Huacheng Wang , Weineng Chen , Fengyin Liang , Haifan Kong , Tara S.R. Chen , Lishan Lin , Hua Hong , Zhong Pei","doi":"10.1016/j.expneurol.2024.115020","DOIUrl":"10.1016/j.expneurol.2024.115020","url":null,"abstract":"<div><div>Cognitive impairment is often found at the acute stages and sequelae of coronavirus disease 2019 (COVID-19), and the underlying mechanisms remain unclear. The S1 protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be a cause of cognitive impairment associated with COVID-19. The nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome and neuroinflammation play important roles in Alzheimer's disease (AD) with cognitive impairment. However, their roles remain unknown in COVID-19 with cognitive impairment. We stimulated BV2 cells with S1 protein <em>in vitro</em> and injected the hippocampi of wild-type (WT) mice, NLRP3 knockout (KO), and microglia NLRP3 KO mice <em>in vivo</em> with S1 protein to induce cognitive impairment. We assessed exploratory behavior as associative memory using novel object recognition and Morris water maze tests. Neuroinflammation was analyzed using immunofluorescence and western blotting to detect inflammatory markers. Co-localized NLRP3 and S1 proteins were investigated using confocal microscopy. We found that S1 protein injection led to cognitive impairment, neuronal loss, and neuroinflammation by activating NLRP3 inflammation, and this was reduced by global NLRP3 KO and microglia NLRP3 KO. Furthermore, TAK 242, a specific inhibitor of Toll-like receptor-4, resulted in a significant reduction in NLRP3 and pro-IL-1β in BV2 cells with S1 protein stimulation. These results reveal a distinct mechanism through which the SARS-CoV-2 spike S1 protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115020"},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.expneurol.2024.115019
Jiashuo Zhao , Weixin Xing , Chengyuan Ji , Hongwei Hu , Yuanqing Zhang , Zongqi Wang , Jiangang Liu
Background
Traumatic Brain Injury (TBI) is a multifaceted injury that can cause a wide range of symptoms and impairments, leading to significant effects on brain function. Nucleophosmin 1 (NPM1), a versatile phosphoprotein located in the nucleolus, is being recognized as a possible controller of cellular stress reactions and could be important in reducing neuro dysfunction caused by TBI. However the critical roles of NPM1 in cellular stress in TBI remains unclear.
Methods
We employed a control cortical impact mouse model and a scratch-induced primary neuronal culture model. Hematoxylin and eosin staining was used to evaluate tissue damage and cellular changes, with NPM1 expression in the cortical area assessed through immunofluorescence staining and Western blot analysis. Neuronal morphology was assessed using Nissl staining. Behavioral assessments were performed to evaluate the impact of NPM1 overexpression on neurobehavioral results in TBI mice. Mitochondrial function was assessed using an Extracellular Flux Analyzer.
Results
Following TBI, an increase in NPM1 expression was observed, with a peak at 72 h post-injury. Increased levels of NPM1 resulted in decreased neuronal cell death, as shown by Nissl staining, and lower levels of Caspase 8, APE1, H2AX, and 8-OHDG expression, indicating a reduction in DNA damage. NPM1 overexpression also resulted in improved neurobehavioral outcomes, characterized by decreased neurological deficits and enhanced motor function post-TBI. Additionally, in vitro, scratch-induction experiments revealed that NPM1 overexpression mitigated mitochondrial damage, as evidenced by the downregulation of P53, BCL2, and Cyto C expression levels and improvements in mitochondrial respiratory function.
Conclusion
These findings suggest NPM1 as a promising target for developing interventions to alleviate TBI-related cellular stress and promote neuronal survival.
{"title":"Nucleophosmin 1 overexpression enhances neuroprotection by attenuating cellular stress in traumatic brain injury","authors":"Jiashuo Zhao , Weixin Xing , Chengyuan Ji , Hongwei Hu , Yuanqing Zhang , Zongqi Wang , Jiangang Liu","doi":"10.1016/j.expneurol.2024.115019","DOIUrl":"10.1016/j.expneurol.2024.115019","url":null,"abstract":"<div><h3>Background</h3><div>Traumatic Brain Injury (TBI) is a multifaceted injury that can cause a wide range of symptoms and impairments, leading to significant effects on brain function. Nucleophosmin 1 (NPM1), a versatile phosphoprotein located in the nucleolus, is being recognized as a possible controller of cellular stress reactions and could be important in reducing neuro dysfunction caused by TBI. However the critical roles of NPM1 in cellular stress in TBI remains unclear.</div></div><div><h3>Methods</h3><div>We employed a control cortical impact mouse model and a scratch-induced primary neuronal culture model. Hematoxylin and eosin staining was used to evaluate tissue damage and cellular changes, with NPM1 expression in the cortical area assessed through immunofluorescence staining and Western blot analysis. Neuronal morphology was assessed using Nissl staining. Behavioral assessments were performed to evaluate the impact of NPM1 overexpression on neurobehavioral results in TBI mice. Mitochondrial function was assessed using an Extracellular Flux Analyzer.</div></div><div><h3>Results</h3><div>Following TBI, an increase in NPM1 expression was observed, with a peak at 72 h post-injury. Increased levels of NPM1 resulted in decreased neuronal cell death, as shown by Nissl staining, and lower levels of Caspase 8, APE1, H2AX, and 8-OHDG expression, indicating a reduction in DNA damage. NPM1 overexpression also resulted in improved neurobehavioral outcomes, characterized by decreased neurological deficits and enhanced motor function post-TBI. Additionally, <em>in vitro</em>, scratch-induction experiments revealed that NPM1 overexpression mitigated mitochondrial damage, as evidenced by the downregulation of P53, BCL2, and Cyto C expression levels and improvements in mitochondrial respiratory function.</div></div><div><h3>Conclusion</h3><div>These findings suggest NPM1 as a promising target for developing interventions to alleviate TBI-related cellular stress and promote neuronal survival.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115019"},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-17DOI: 10.1016/j.expneurol.2024.114989
Yi Rong , Yinbo Kang , Jie Wen , Qian Gong , Wenlong Zhang , Ke Sun , Weibing Shuang
Background
A critical aspect affecting the quality of life in Traumatic spinal cord injury (TSCI) patients is bladder dysfunction. Metabolities in arachidonic acid are crucial lipid signaling molecules involved innumerous physiological processes. In this study, We are the first use eicosanoid metabolomics detrusor contraction examine, to assess the effect of the arachidonic acid metabolic in bladder dysfunction following TSCI. In additon, we explore the time of inflammatory and function changes in bladder tissue.
Methods
Adult male Sprague-Dawley rats were subjected to improved Weight Drop method surgeries. Detrusor contraction examination, urodynamic examination, eicosanoid metabolomics, transmission electron microscopy, Elisa and histological staining were performed to assess the change of inflammatory, metabolic and function variation over time after TSCI.
Results
Following TSCI, before the variations of bladder function, inflammatory changes including the increase of inflammatory factors, mitochondrial damage, and slight lipid peroxidation, occurred in bladder tissue. And the inflammatory changes gradually decreases over time. However, From the third day after TSCI, secondary lesions appeared in bladder tissue. Not only did inflammation-related indexes increase again, the degree of mitochondrial damage and lipid peroxidation increased, but also the contractility of detrusor began to change significantly. We also found that the content of metabolites in arachidonic acid metabolic pathway and the degree of detrusor contractility change showed a strong correlation. In addition, we found that rats had moved beyond the spinal shock stage on the seventh day after TSCI.
Conclusion
Altogether, we are the first to demonstrate that abnormal arachidonic acid metabolism plays an important role in bladder dysfunction after TSCI. We also demonstrate that 3d is a critical juncture for changes in rat bladder tissue, which indicates it is an important juncture in the treatment of neurogenic bladder.
{"title":"Time-dependent arachidonic acid metabolism and functional changes in rats bladder tissue after suprasacral spinal cord injury","authors":"Yi Rong , Yinbo Kang , Jie Wen , Qian Gong , Wenlong Zhang , Ke Sun , Weibing Shuang","doi":"10.1016/j.expneurol.2024.114989","DOIUrl":"10.1016/j.expneurol.2024.114989","url":null,"abstract":"<div><h3>Background</h3><div>A critical aspect affecting the quality of life in Traumatic spinal cord injury (TSCI) patients is bladder dysfunction. Metabolities in arachidonic acid are crucial lipid signaling molecules involved innumerous physiological processes. In this study, We are the first use eicosanoid metabolomics detrusor contraction examine, to assess the effect of the arachidonic acid metabolic in bladder dysfunction following TSCI. In additon, we explore the time of inflammatory and function changes in bladder tissue.</div></div><div><h3>Methods</h3><div>Adult male Sprague-Dawley rats were subjected to improved Weight Drop method surgeries. Detrusor contraction examination, urodynamic examination, eicosanoid metabolomics, transmission electron microscopy, Elisa and histological staining were performed to assess the change of inflammatory, metabolic and function variation over time after TSCI.</div></div><div><h3>Results</h3><div>Following TSCI, before the variations of bladder function, inflammatory changes including the increase of inflammatory factors, mitochondrial damage, and slight lipid peroxidation, occurred in bladder tissue. And the inflammatory changes gradually decreases over time. However, From the third day after TSCI, secondary lesions appeared in bladder tissue. Not only did inflammation-related indexes increase again, the degree of mitochondrial damage and lipid peroxidation increased, but also the contractility of detrusor began to change significantly. We also found that the content of metabolites in arachidonic acid metabolic pathway and the degree of detrusor contractility change showed a strong correlation. In addition, we found that rats had moved beyond the spinal shock stage on the seventh day after TSCI.</div></div><div><h3>Conclusion</h3><div>Altogether, we are the first to demonstrate that abnormal arachidonic acid metabolism plays an important role in bladder dysfunction after TSCI. We also demonstrate that 3d is a critical juncture for changes in rat bladder tissue, which indicates it is an important juncture in the treatment of neurogenic bladder.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 114989"},"PeriodicalIF":4.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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