Molecular Neurobiology最新文献

PD-Like Pathogenesis in Caenorhabditis elegans Intestinally Infected with Nocardia farcinica and the Underlying Molecular Mechanisms. 肠道感染远志野卡氏菌的秀丽隐杆线虫的 PD 类发病机制及其分子机理

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-03-28 DOI: 10.1007/s12035-024-04076-w

Wenwen Liu, Wenhui Zhou, Peiji Zhao, Tingting Wu, Huan Gu, Yixin Li, Chidi Zhong, Hua Bai, Ninghui Zhao, Xiaowei Huang

{"title":"PD-Like Pathogenesis in Caenorhabditis elegans Intestinally Infected with Nocardia farcinica and the Underlying Molecular Mechanisms.","authors":"Wenwen Liu, Wenhui Zhou, Peiji Zhao, Tingting Wu, Huan Gu, Yixin Li, Chidi Zhong, Hua Bai, Ninghui Zhao, Xiaowei Huang","doi":"10.1007/s12035-024-04076-w","DOIUrl":"10.1007/s12035-024-04076-w","url":null,"abstract":"Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein (α-syn) and the loss of dopaminergic neurons. Although microbial infection has been implicated in the pathogenesis of PD, the associated virulence factors and the underlying molecular mechanisms require further elucidation. Here, we found that intestinal infection with Nocardia farcinica induced a series of PD-like symptoms in Caenorhabditis elegans, such as the accelerated degeneration of dopaminergic neurons, impaired locomotion capacity, and enhanced α-syn aggregation, through the disturbance of mitochondrial functions. To identify the potential virulence factors involved in these effects, we knocked out the nbtB/C and nbtS genes in N. farcinica, which are localized in the gene clusters responsible for nocobactin biosynthesis. The deletion of either gene partially rescued the degenerative effects of wild-type N. farcinica on dopaminergic neurons by attenuating mitochondrial dysfunction. LC-MS analysis further identified a decrease in the abundance of several siderophores in the two mutants, including nocobactin NA-a, nocobactin NA-b, and nocardimicin B. Collectively, our results demonstrated that intestinal N. farcinica infection in C. elegans facilitates PD-like pathogenesis and provides novel evidence for the involvement of pathogenic bacteria in neurodegenerative diseases via non-neuroinvasive mechanisms.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"2641-2654"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318743","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}

引用次数: 0

Brain Proteome Profiling Reveals Common and Divergent Signatures in Parkinson's Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy. 大脑蛋白质组图谱分析揭示帕金森病、多系统萎缩症和进行性核上性麻痹的共性和差异特征

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-08-21 DOI: 10.1007/s12035-024-04422-y

Fiona Dick, Gard Aasmund Skulstad Johanson, Ole-Bjørn Tysnes, Guido Alves, Christian Dölle, Charalampos Tzoulis

{"title":"Brain Proteome Profiling Reveals Common and Divergent Signatures in Parkinson's Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy.","authors":"Fiona Dick, Gard Aasmund Skulstad Johanson, Ole-Bjørn Tysnes, Guido Alves, Christian Dölle, Charalampos Tzoulis","doi":"10.1007/s12035-024-04422-y","DOIUrl":"10.1007/s12035-024-04422-y","url":null,"abstract":"The molecular pathogenesis of degenerative parkinsonisms, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and Multiple system atrophy (MSA), remains largely unknown. To gain novel insight into molecular processes associated with these diseases, we conducted a proteome-wide expression study in prefrontal cortex tissue from a cohort of 181 individuals, comprising PD (N = 73), PSP (N = 18), MSA (N = 17) and healthy control (N = 73). Using marker gene profiles, we first assess the cellular composition of the samples and, subsequently, identify distinct protein signatures for each disease, while correcting for cell composition. Our findings indicate that all three diseases are characterized by a structural and/or functional loss of deep cortical neurons, while PD exhibits an additional decrease in somatostatin-expressing interneurons, as well as in endothelial cells. Differential protein expression analysis identified multiple proteins and pathways with disease-specific expression, some of which have previously been associated with parkinsonism or neurodegeneration in general. Notably, we observed a strong mitochondrial signature which was present in both PD and PSP, albeit of a different composition and most pronounced in PSP, but not in MSA where immunological/inflammation-related pathways dominated. Additionally, we identified protein signatures associated with the severity of α-synuclein pathology in PD and showed that these are highly enriched in an upregulation of mitochondrial processes, specifically related to oxidative phosphorylation and in particular respiratory complexes I and IV. We identify multiple novel signatures of protein expression, associated with PD, PSP, and MSA, as well as with the severity of α-synuclein pathology in the PD brain.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"2801-2816"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009041","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}

引用次数: 0

Apolipoprotein E in Alzheimer's Disease: Focus on Synaptic Function and Therapeutic Strategy. 阿尔茨海默病中的载脂蛋白 E：聚焦突触功能和治疗策略。

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-08-31 DOI: 10.1007/s12035-024-04449-1

Longjie Qu, Shuai Xu, Zhen Lan, Shuang Fang, Yun Xu, Xiaolei Zhu

引用次数: 0

Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases. 开启希望：调节 Wnt 通路治疗神经退行性疾病的治疗进展和方法》。

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-09-23 DOI: 10.1007/s12035-024-04462-4

Navid Faraji, Negar Ebadpour, Mohammad Abavisani, Ali Gorji

{"title":"Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases.","authors":"Navid Faraji, Negar Ebadpour, Mohammad Abavisani, Ali Gorji","doi":"10.1007/s12035-024-04462-4","DOIUrl":"10.1007/s12035-024-04462-4","url":null,"abstract":"Neurodegenerative diseases (NDs) are conditions characterized by sensory, motor, and cognitive impairments due to alterations in the structure and function of neurons in the central nervous system (CNS). Despite their widespread occurrence, the exact causes of NDs remain largely elusive, and existing treatments fall short in efficacy. The Wnt signaling pathway is an emerging molecular pathway that has been linked to the development and progression of various NDs. Wnt signaling governs numerous cellular processes, such as survival, polarity, proliferation, differentiation, migration, and fate specification, via a complex network of proteins. In the adult CNS, Wnt signaling regulates synaptic transmission, plasticity, memory formation, neurogenesis, neuroprotection, and neuroinflammation, all essential for maintaining neuronal function and integrity. Dysregulation of both canonical and non-canonical Wnt signaling pathways contributes to neurodegeneration through various mechanisms, such as amyloid-β accumulation, tau protein hyperphosphorylation, dopaminergic neuron degeneration, and synaptic dysfunction, prompting investigations into Wnt modulation as a therapeutic target to restore neuronal function and prevent or delay neurodegenerative processes. Modulating Wnt signaling has the potential to restore neuronal function and impede or postpone neurodegenerative processes, offering a therapeutic approach for targeting NDs. In this article, the current knowledge about how Wnt signaling works in Alzheimer's disease and Parkinson's disease is discussed. Our study aims to explore the molecular mechanisms, recent discoveries, and challenges involved in developing Wnt-based therapies.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"3630-3652"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308084","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}

引用次数: 0

Vinpocetine Ameliorates Neuronal Injury After Cold-Induced Traumatic Brain Injury in Mice. 长春西汀可改善小鼠冷诱导创伤性脑损伤后的神经元损伤

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-10-03 DOI: 10.1007/s12035-024-04515-8

Hayriye E Yelkenci, Zehra Degirmenci, Halil I Koc, Sevban Bayirli, Saltuk B Baltaci, Serdar Altunay, Nevin Oztekin, Mehmet Kocak, Ertugrul Kilic, Mustafa C Beker

{"title":"Vinpocetine Ameliorates Neuronal Injury After Cold-Induced Traumatic Brain Injury in Mice.","authors":"Hayriye E Yelkenci, Zehra Degirmenci, Halil I Koc, Sevban Bayirli, Saltuk B Baltaci, Serdar Altunay, Nevin Oztekin, Mehmet Kocak, Ertugrul Kilic, Mustafa C Beker","doi":"10.1007/s12035-024-04515-8","DOIUrl":"10.1007/s12035-024-04515-8","url":null,"abstract":"Traumatic brain injury (TBI), also known as intracranial injury, is a common condition with the highest incidence rate among neurodegenerative disorders and poses a significant public health burden. Various methods are used in the treatment of TBI, but the effects of cold-induced traumatic brain injury have not been thoroughly studied. In this context, vinpocetine (VPN), derived from Vinca minor, exhibits notable anti-inflammatory and antioxidant properties. VPN is known for its neuroprotective role and is generally utilized for treating various neurodegenerative disorders. However, the function of VPN after cold-induced TBI needs to be studied in more detail. This study aims to investigate the neuroprotective effects of VPN at varying doses (5 mg/kg or 10 mg/kg) after cold-induced TBI. C57BL/6 mice were sacrificed 2 or 28 days after cold-induced TBI. Results indicate that VPN administration significantly reduces brain infarct volume, brain swelling, blood-brain barrier disruption, and DNA fragmentation in a dose-dependent manner. Additionally, VPN enhances neuronal survival in the ipsilesional cortex. In the long term, VPN treatment (5 mg/kg/day or 10 mg/kg/day, initiated 48 h post-TBI) improved locomotor activity, cell proliferation, neurogenesis, and decreased whole brain atrophy, specifically motor cortex atrophy. We performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to elucidate the underlying mechanisms to profile proteins and signaling pathways influenced by prolonged VPN treatment post-TBI. Notably, we found that 192 different proteins were significantly altered by VPN treatment, which is a matter of further investigation for the development of therapeutic targets. Our study has shown that VPN may have a neuroprotective role in cold-induced TBI.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"3956-3972"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365814","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}

引用次数: 0

A Screen of Plant-Based Natural Products Revealed That Quercetin Prevents Pyroglutamylated Amyloid-β (Aβ3(pE)-42) Uptake in Astrocytes As Well As Resulting Astrogliosis and Synaptic Dysfunction. 对植物性天然产物的筛选发现，槲皮素能防止焦谷氨酰化淀粉样蛋白-β（Aβ3(pE)-42）在星形胶质细胞中的摄取以及导致星形胶质细胞增生和突触功能障碍。在星形胶质细胞中的摄取以及由此导致的星形胶质细胞增生和突触功能障碍。

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-09-25 DOI: 10.1007/s12035-024-04509-6

Helene Arndt, Mark Bachurski, PingAn Yuanxiang, Katrin Franke, Ludger A Wessjohann, Michael R Kreutz, Katarzyna M Grochowska

{"title":"A Screen of Plant-Based Natural Products Revealed That Quercetin Prevents Pyroglutamylated Amyloid-β (Aβ3(pE)-42) Uptake in Astrocytes As Well As Resulting Astrogliosis and Synaptic Dysfunction.","authors":"Helene Arndt, Mark Bachurski, PingAn Yuanxiang, Katrin Franke, Ludger A Wessjohann, Michael R Kreutz, Katarzyna M Grochowska","doi":"10.1007/s12035-024-04509-6","DOIUrl":"10.1007/s12035-024-04509-6","url":null,"abstract":"Two connected histopathological hallmarks of Alzheimer's disease (AD) are chronic neuroinflammation and synaptic dysfunction. The accumulation of the most prevalent posttranslationally modified form of Aβ1-42, pyroglutamylated amyloid-β (Aβ3(pE)-42) in astrocytes is directly linked to glial activation and the release of proinflammatory cytokines that in turn contribute to early synaptic dysfunction in AD. At present, the mechanisms of Aβ3(pE)-42 uptake to astrocytes are unknown and pharmacological interventions that interfere with this process are not available. Here we developed a simple screening assay to identify substances from a plant extract library that prevent astroglial Aβ3(pE)-42 uptake. We first show that this approach yields valid and reproducible results. Second, we show endocytosis of Aβ3(pE)-42 oligomers by astrocytes and that quercetin, a plant flavonol, is effective to specifically block astrocytic buildup of oligomeric Aβ3(pE)-42. Importantly, quercetin does not induce a general impairment of endocytosis. However, it efficiently protects against early synaptic dysfunction following exogenous Aβ3(pE)-42 application.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"3730-3745"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350312","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}

引用次数: 0

Chronically Low NMNAT2 Expression Causes Sub-lethal SARM1 Activation and Altered Response to Nicotinamide Riboside in Axons. 慢性 NMNAT2 低表达导致亚致死性 SARM1 激活和轴突对烟酰胺核苷的反应改变

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-10-01 DOI: 10.1007/s12035-024-04480-2

Christina Antoniou, Andrea Loreto, Jonathan Gilley, Elisa Merlini, Giuseppe Orsomando, Michael P Coleman

{"title":"Chronically Low NMNAT2 Expression Causes Sub-lethal SARM1 Activation and Altered Response to Nicotinamide Riboside in Axons.","authors":"Christina Antoniou, Andrea Loreto, Jonathan Gilley, Elisa Merlini, Giuseppe Orsomando, Michael P Coleman","doi":"10.1007/s12035-024-04480-2","DOIUrl":"10.1007/s12035-024-04480-2","url":null,"abstract":"Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an endogenous axon survival factor that maintains axon health by blocking activation of the downstream pro-degenerative protein SARM1 (sterile alpha and TIR motif containing protein 1). While complete absence of NMNAT2 in mice results in extensive axon truncation and perinatal lethality, the removal of SARM1 completely rescues these phenotypes. Reduced levels of NMNAT2 can be compatible with life; however, they compromise axon development and survival. Mice born expressing sub-heterozygous levels of NMNAT2 remain overtly normal into old age but develop axonal defects in vivo and in vitro as well as behavioural phenotypes. Therefore, it is important to examine the effects of constitutively low NMNAT2 expression on SARM1 activation and disease susceptibility. Here we demonstrate that chronically low NMNAT2 levels reduce prenatal viability in mice in a SARM1-dependent manner and lead to sub-lethal SARM1 activation in morphologically intact axons of superior cervical ganglion (SCG) primary cultures. This is characterised by a depletion in NAD(P) and compromised neurite outgrowth. We also show that chronically low NMNAT2 expression reverses the NAD-enhancing effect of nicotinamide riboside (NR) in axons in a SARM1-dependent manner. These data indicate that low NMNAT2 levels can trigger sub-lethal SARM1 activation which is detectable at the molecular level and could predispose to human axonal disorders.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"3903-3917"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350316","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}

引用次数: 0

Causal Relationships Between Retinal Diseases and Psychiatric Disorders Have Implications for Precision Psychiatry. 视网膜疾病与精神障碍之间的因果关系对精准精神病学的影响

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-09-06 DOI: 10.1007/s12035-024-04456-2

Zicheng Zhang, Siqi Bao, Dongxue Yan, Modi Zhai, Jia Qu, Meng Zhou

{"title":"Causal Relationships Between Retinal Diseases and Psychiatric Disorders Have Implications for Precision Psychiatry.","authors":"Zicheng Zhang, Siqi Bao, Dongxue Yan, Modi Zhai, Jia Qu, Meng Zhou","doi":"10.1007/s12035-024-04456-2","DOIUrl":"10.1007/s12035-024-04456-2","url":null,"abstract":"Observational studies and clinical trials have reported potential associations between retinal diseases and psychiatric disorders. However, the causal associations between them have remained elusive. In this study, we used bi-directional two-sample Mendelian randomization (MR) analysis to explore unconfounded causal relationships between retinal diseases and psychiatric disorders using large-scale genome-wide association study (GWAS) summary statistics of over 500,000 participants of European ancestry from the FinnGen project, the Psychiatric Genomics Consortium, the European Bioinformatics Institute, and the UK Biobank. Our MR analysis revealed significant causal relationships between major retinal diseases and specific psychiatric disorders. Specifically, susceptibility to dry age-related macular degeneration was associated with a reduced risk of anorexia nervosa (OR = 0.970; 95% CI = 0.930 ~ 0.994; P = 0.025). Furthermore, we found some evidence that exposure to diabetic retinopathy was associated with an increased risk of schizophrenia (OR = 1.021; 95% CI 1.012 ~ 1.049; P = 0.001), and exposure to retinal detachments and breaks was associated with an increased risk of attention deficit hyperactivity disorder (OR = 1.190; 95% CI 1.063 ~ 1.333; P = 0.003). These causal relationships were not confounded by biases of pleiotropy and reverse causation. Our study highlights the importance of preventing and managing retinal disease as a potential avenue for improving the prevention, management and treatment of major psychiatric disorders.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"3182-3194"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140467","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}

引用次数: 0

Microglia Promote Lymphangiogenesis Around the Spinal Cord Through VEGF-C/VEGFR3-Dependent Autophagy and Polarization After Acute Spinal Cord Injury. 急性脊髓损伤后，小胶质细胞通过 VEGF-C/VEGFR3 依赖性自噬和极化促进脊髓周围淋巴管生成

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-08-19 DOI: 10.1007/s12035-024-04437-5

Yeyang Xian, Jie Liu, Mengxuan Dai, Wensheng Zhang, Minye He, Zhengnong Wei, Yutao Jiang, Shiyong Le, Zhuoang Lin, Shuai Tang, Yunfei Zhou, Liming Dong, Jinzheng Liang, Jie Zhang, Liang Wang

{"title":"Microglia Promote Lymphangiogenesis Around the Spinal Cord Through VEGF-C/VEGFR3-Dependent Autophagy and Polarization After Acute Spinal Cord Injury.","authors":"Yeyang Xian, Jie Liu, Mengxuan Dai, Wensheng Zhang, Minye He, Zhengnong Wei, Yutao Jiang, Shiyong Le, Zhuoang Lin, Shuai Tang, Yunfei Zhou, Liming Dong, Jinzheng Liang, Jie Zhang, Liang Wang","doi":"10.1007/s12035-024-04437-5","DOIUrl":"10.1007/s12035-024-04437-5","url":null,"abstract":"Reducing secondary injury is a key focus in the field of spinal cord injury (SCI). Recent studies have revealed the role of lymphangiogenesis in reducing secondary damage to central nerve. However, the mechanism of lymphangiogenesis is not yet clear. Macrophages have been shown to play an important role in peripheral tissue lymphangiogenesis. Microglia is believed to play a role similar to macrophages in the central nervous system (CNS); we hypothesized that there was a close relationship between microglia and central nerve system lymphangiogenesis. Herein, we used an in vivo model of SCI to explored the relationship between microglia and spinal cord lymphangiogenesis and further investigated the polarization of microglia and its role in promoting spinal cord lymphangiogenesis by a series of in vitro experiments. The current study elucidated for the first time the relationship between microglia and lymphangiogenesis around the spinal cord after SCI. Classical activated (M1) microglia can promote lymphangiogenesis by secreting VEGF-C which further increases polarization and secretion of lymphatic growth factor by activating VEGFR3. The VEGF-C/VEGFR3 pathway activation downregulates microglia autophagy, thereby regulating the microglia phenotype. These results indicate that M1 microglia promote lymphangiogenesis after SCI, and activated VEGF-C/VEGFR3 signaling promotes M1 microglia polarization by inhibiting autophagy, thereby facilitates lymphangiogenesis.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"2740-2755"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000339","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}

引用次数: 0

Downregulation of Fidgetin-Like 2 Increases Microglial Function: The Relationship Between Microtubules, Morphology, and Activity. 下调 Fidgetin-Like 2 可增强小胶质细胞功能：微管、形态和活动之间的关系

IF 4.6 2区医学

Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-08-19 DOI: 10.1007/s12035-024-04404-0

Austin N Smith, Alison Gregor, Lisa Baker, David J Sharp, Kimberly R Byrnes

{"title":"Downregulation of Fidgetin-Like 2 Increases Microglial Function: The Relationship Between Microtubules, Morphology, and Activity.","authors":"Austin N Smith, Alison Gregor, Lisa Baker, David J Sharp, Kimberly R Byrnes","doi":"10.1007/s12035-024-04404-0","DOIUrl":"10.1007/s12035-024-04404-0","url":null,"abstract":"The microtubule cytoskeleton regulates microglial morphology, motility, and effector functions. The microtubule-severing enzyme, fidgetin-like 2 (FL2), negatively regulates cell motility and nerve regeneration, making it a promising therapeutic target for central nervous system injury. Microglia perform important functions in response to inflammation and injury, but how FL2 affects microglia is unclear. In this study, we investigated the role of FL2 in microglial morphology and injury responses in vitro. We first determined that the pro-inflammatory stimulus, lipopolysaccharide (LPS), induced a dose- and time-dependent reduction in FL2 expression associated with reduced microglial ramification. We then administered nanoparticle-encapuslated FL2 siRNA to knockdown FL2 and assess microglial functions compared to negative control siRNA and vehicle controls. Time-lapse live-cell microscopy showed that FL2 knockdown increased the velocity of microglial motility. After incubation with fluorescently labeled IgG-opsonized beads, FL2 knockdown increased phagocytosis. Microglia were exposed to low-dose LPS after nanoparticle treatment to model injury-induced cytokine secretion. FL2 knockdown enhanced LPS-induced cytokine secretion of IL-1α, IL-1β, and TNFα. These results identify FL2 as a regulator of microglial morphology and suggest that FL2 can be targeted to increase or accelerate microglial injury responses.","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"2726-2739"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004812","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}

引用次数: 0