Pub Date : 2025-03-01Epub Date: 2025-01-27DOI: 10.1016/j.mcn.2025.103994
Ruqayya Afridi , Anup Bhusal , Seung Eun Lee , Eun Mi Hwang , Hoon Ryu , Jong-Heon Kim , Kyoungho Suk
Microglia-mediated neuroinflammation has been implicated in the neuropathology of traumatic brain injuries (TBI). Recently, the expression of interleukin-2-inducible T-cell kinase (ITK) has been detected in brain microglia, regulating their inflammatory activities. However, the role of microglial ITK in TBI has not been investigated. In this study, we demonstrate that ITK expression and activation are upregulated in microglia following an injury caused by controlled cortical impact (CCI) – a mouse model of TBI. Pharmacological inhibition of ITK protein or knockdown of microglial ITK gene expression using adeno-associated virus mitigates neuroinflammation and improves neurological outcomes in the CCI model. Additionally, ITK mRNA expression was found to be increased in the brains of patients with chronic traumatic encephalopathy. An ITK inhibitor reduced the activation of inflammatory responses in both human and mouse microglia in vitro. Collectively, these results suggest that microglial ITK plays a pivotal role in neuroinflammation and mediating behavioral deficits following TBI. Thus, targeting the signaling pathway of microglial ITK may exert protective effects by alleviating neuroinflammation associated with TBI.
{"title":"A microglial kinase ITK mediating neuroinflammation and behavioral deficits in traumatic brain injury","authors":"Ruqayya Afridi , Anup Bhusal , Seung Eun Lee , Eun Mi Hwang , Hoon Ryu , Jong-Heon Kim , Kyoungho Suk","doi":"10.1016/j.mcn.2025.103994","DOIUrl":"10.1016/j.mcn.2025.103994","url":null,"abstract":"<div><div>Microglia-mediated neuroinflammation has been implicated in the neuropathology of traumatic brain injuries (TBI). Recently, the expression of interleukin-2-inducible T-cell kinase (ITK) has been detected in brain microglia, regulating their inflammatory activities. However, the role of microglial ITK in TBI has not been investigated. In this study, we demonstrate that ITK expression and activation are upregulated in microglia following an injury caused by controlled cortical impact (CCI) – a mouse model of TBI. Pharmacological inhibition of ITK protein or knockdown of microglial ITK gene expression using adeno-associated virus mitigates neuroinflammation and improves neurological outcomes in the CCI model. Additionally, ITK mRNA expression was found to be increased in the brains of patients with chronic traumatic encephalopathy. An ITK inhibitor reduced the activation of inflammatory responses in both human and mouse microglia in vitro. Collectively, these results suggest that microglial ITK plays a pivotal role in neuroinflammation and mediating behavioral deficits following TBI. Thus, targeting the signaling pathway of microglial ITK may exert protective effects by alleviating neuroinflammation associated with TBI.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103994"},"PeriodicalIF":2.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-09-10DOI: 10.1016/j.mcn.2024.103969
Ericks Sousa Soares , Letícia Yoshitome Queiroz , Ellen Gerhardt , Rui Daniel S. Prediger , Tiago Fleming Outeiro , Helena Iturvides Cimarosti
SUMOylation is a post-translational modification essential for various biological processes. SUMO proteins bind to target substrates in a three-step enzymatic pathway, which is rapidly reversible by the action of specific proteases, known as SENPs. Studies have shown that SUMOylation is dysregulated in several human disorders, including neurodegenerative diseases that are characterized by the progressive loss of neurons, mitochondrial dysfunction, deficits in autophagy, and oxidative stress. Considering the potential neuroprotective roles of SUMOylation, the aim of this study was to investigate the effects of SENP3 knockdown in H4 neuroglioma cells exposed to rotenone, an in vitro model of cytotoxicity that mimics dopaminergic loss in Parkinson's disease (PD). The current data show that SENP3 knockdown increases SUMO-2/3 conjugates, which is accompanied by reduced levels of the mitochondrial fission protein Drp1 and increased levels of the mitochondrial fusion protein OPA1. Of high interest, SENP3 knockdown prevented rotenone-induced superoxide production and cellular death. Taken together, these findings highlight the importance of SUMOylation in maintaining mitochondrial homeostasis and the neuroprotective potential of this modification in PD.
{"title":"SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease","authors":"Ericks Sousa Soares , Letícia Yoshitome Queiroz , Ellen Gerhardt , Rui Daniel S. Prediger , Tiago Fleming Outeiro , Helena Iturvides Cimarosti","doi":"10.1016/j.mcn.2024.103969","DOIUrl":"10.1016/j.mcn.2024.103969","url":null,"abstract":"<div><p>SUMOylation is a post-translational modification essential for various biological processes. SUMO proteins bind to target substrates in a three-step enzymatic pathway, which is rapidly reversible by the action of specific proteases, known as SENPs. Studies have shown that SUMOylation is dysregulated in several human disorders, including neurodegenerative diseases that are characterized by the progressive loss of neurons, mitochondrial dysfunction, deficits in autophagy, and oxidative stress. Considering the potential neuroprotective roles of SUMOylation, the aim of this study was to investigate the effects of SENP3 knockdown in H4 neuroglioma cells exposed to rotenone, an <em>in vitro</em> model of cytotoxicity that mimics dopaminergic loss in Parkinson's disease (PD). The current data show that SENP3 knockdown increases SUMO-2/3 conjugates, which is accompanied by reduced levels of the mitochondrial fission protein Drp1 and increased levels of the mitochondrial fusion protein OPA1. Of high interest, SENP3 knockdown prevented rotenone-induced superoxide production and cellular death. Taken together, these findings highlight the importance of SUMOylation in maintaining mitochondrial homeostasis and the neuroprotective potential of this modification in PD.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103969"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-08-22DOI: 10.1016/j.mcn.2024.103959
Sen Shang, Leilei Wang, Xiaoyun Lu
β-Hydroxybutyrate (BHB) has been reported to exert neuroprotective functions and is considered a promising treatment for neurodegenerative diseases such as Parkinson's and Alzheimer's. Numerous studies have revealed BHB's multifaceted roles, including anti-senescence, anti-oxidative, and anti-inflammatory activities. However, the underlying mechanisms warrant further investigation. Astrocytes, the most abundant glial cells in the central nervous system, play a pivotal role in the development and progression of neurodegenerative diseases. While BHB is known to alter neuronal metabolism and function, its effects on astrocytes remain poorly understood. In this study, we conducted transcriptome sequencing analysis to identify differentially expressed genes induced by BHB in astrocytes and found that the gene Solute carrier family 1 member 3 (Slc1a3), encoding the glutamate transporter EAAT1, was significantly upregulated by BHB treatment. Cellular and animal-based experiments confirmed an increase in EAAT1 protein expression in primary astrocytes and the hippocampus of mice treated with BHB. This upregulation may be due to the activation of the Ca2+/CAMKII pathway by BHB. Furthermore, BHB improved astrocytes' glutamate uptake and partially restored neuronal viability impaired by glutamate-induced excitotoxicity when astrocytes were functionalized. Our results suggest that BHB may alleviate neuronal damage caused by excessive glutamate by enhancing the glutamate absorption and uptake capacity of astrocytes. This study proposes a novel mechanism for the neuroprotective effects of BHB and reinforces its beneficial impact on the central nervous system (CNS).
{"title":"β-Hydroxybutyrate enhances astrocyte glutamate uptake through EAAT1 expression regulation","authors":"Sen Shang, Leilei Wang, Xiaoyun Lu","doi":"10.1016/j.mcn.2024.103959","DOIUrl":"10.1016/j.mcn.2024.103959","url":null,"abstract":"<div><p>β-Hydroxybutyrate (BHB) has been reported to exert neuroprotective functions and is considered a promising treatment for neurodegenerative diseases such as Parkinson's and Alzheimer's. Numerous studies have revealed BHB's multifaceted roles, including anti-senescence, anti-oxidative, and anti-inflammatory activities. However, the underlying mechanisms warrant further investigation. Astrocytes, the most abundant glial cells in the central nervous system, play a pivotal role in the development and progression of neurodegenerative diseases. While BHB is known to alter neuronal metabolism and function, its effects on astrocytes remain poorly understood. In this study, we conducted transcriptome sequencing analysis to identify differentially expressed genes induced by BHB in astrocytes and found that the gene Solute carrier family 1 member 3 (Slc1a3), encoding the glutamate transporter EAAT1, was significantly upregulated by BHB treatment. Cellular and animal-based experiments confirmed an increase in EAAT1 protein expression in primary astrocytes and the hippocampus of mice treated with BHB. This upregulation may be due to the activation of the Ca<sup>2+</sup>/CAMKII pathway by BHB. Furthermore, BHB improved astrocytes' glutamate uptake and partially restored neuronal viability impaired by glutamate-induced excitotoxicity when astrocytes were functionalized. Our results suggest that BHB may alleviate neuronal damage caused by excessive glutamate by enhancing the glutamate absorption and uptake capacity of astrocytes. This study proposes a novel mechanism for the neuroprotective effects of BHB and reinforces its beneficial impact on the central nervous system (CNS).</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103959"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-04DOI: 10.1016/j.mcn.2024.103975
Fotis Andromidas , Brooke E. Mackinnon , Abigail J. Myers , Melanie M. Shaffer , Ayat Brahimi , Saeid Atashpanjeh , Tiana L. Vazquez , Timmy Le , Evan R. Jellison , Susan Staurovsky , Andrew O. Koob
Astrocytes are tasked with regulating the synaptic environment. Early stages of various neurodegenerative diseases are characterized by synapse loss, and astrocytic atrophy and dysfunction has been proposed as a possible cause. α-Synuclein (αS) is a highly expressed neuronal protein located in the synapse that can be released in the extracellular space. Evidence points to astrocytes as being responsible for uptake and degradation of extracellular αS. Therefore, misfolded active fibrillized αS resulting in protein inclusions and aggregates could be due to astrocytic dysfunction. Despite these pathological hallmarks and lines of evidence, the autophagic function of astrocytes in response to monomeric non-active αS to model healthy conditions has not been investigated. Human primary cortical astrocytes were treated with 100 nM of extracellular monomeric non-active αS alone, and in combination with N-terminal binding monomeric γ-synuclein (γS) as a control. Western blot analysis and super resolution imaging of HiLyte-488 labeled αS confirmed successful internalization of αS at 12, 24 and 48 h after treatment, while αS dimers were only observed at 48 h. Western blot analysis also confirmed αS's ability to induce autophagic flux by 48 h. Annexin V/PI flow cytometry results revealed increased early apoptosis at 24 h, but which resolved itself by 48 h, indicating no cell death in cortical astrocytes at all time points, suggesting astrocytes can manage the protein degradation demand of monomeric αS in healthy physiological conditions. Likewise, astrocytes reduced secretion of apolipoprotein (ApoE), a protein involved in pro-inflammatory pathways, synapse regulation, and autophagy by 12 h. Similarly, total c-JUN protein levels, a transcription factor involved in pro-inflammatory pathways increased by 12 h in the nuclear fraction. Therefore, astrocytes are able to respond and degrade αS in healthy physiological conditions, and astrocyte dysfunction could precede detrimental αS accumulation.
{"title":"Astrocytes initiate autophagic flux and maintain cell viability after internalizing non-active native extracellular α-synuclein","authors":"Fotis Andromidas , Brooke E. Mackinnon , Abigail J. Myers , Melanie M. Shaffer , Ayat Brahimi , Saeid Atashpanjeh , Tiana L. Vazquez , Timmy Le , Evan R. Jellison , Susan Staurovsky , Andrew O. Koob","doi":"10.1016/j.mcn.2024.103975","DOIUrl":"10.1016/j.mcn.2024.103975","url":null,"abstract":"<div><div>Astrocytes are tasked with regulating the synaptic environment. Early stages of various neurodegenerative diseases are characterized by synapse loss, and astrocytic atrophy and dysfunction has been proposed as a possible cause. α-Synuclein (αS) is a highly expressed neuronal protein located in the synapse that can be released in the extracellular space. Evidence points to astrocytes as being responsible for uptake and degradation of extracellular αS. Therefore, misfolded active fibrillized αS resulting in protein inclusions and aggregates could be due to astrocytic dysfunction. Despite these pathological hallmarks and lines of evidence, the autophagic function of astrocytes in response to monomeric non-active αS to model healthy conditions has not been investigated. Human primary cortical astrocytes were treated with 100 nM of extracellular monomeric non-active αS alone, and in combination with N-terminal binding monomeric γ-synuclein (γS) as a control. Western blot analysis and super resolution imaging of HiLyte-488 labeled αS confirmed successful internalization of αS at 12, 24 and 48 h after treatment, while αS dimers were only observed at 48 h. Western blot analysis also confirmed αS's ability to induce autophagic flux by 48 h. Annexin V/PI flow cytometry results revealed increased early apoptosis at 24 h, but which resolved itself by 48 h, indicating no cell death in cortical astrocytes at all time points, suggesting astrocytes can manage the protein degradation demand of monomeric αS in healthy physiological conditions. Likewise, astrocytes reduced secretion of apolipoprotein (ApoE), a protein involved in pro-inflammatory pathways, synapse regulation, and autophagy by 12 h. Similarly, total c-JUN protein levels, a transcription factor involved in pro-inflammatory pathways increased by 12 h in the nuclear fraction. Therefore, astrocytes are able to respond and degrade αS in healthy physiological conditions, and astrocyte dysfunction could precede detrimental αS accumulation.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103975"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-31DOI: 10.1016/j.mcn.2024.103978
Hyun Jung Kwon , Hyo Young Jung , Soo Young Choi , In Koo Hwang , Dae Won Kim , Min Jea Shin
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment.
{"title":"TAT-PPA1 protects against oxidative stress-induced loss of dopaminergic neurons","authors":"Hyun Jung Kwon , Hyo Young Jung , Soo Young Choi , In Koo Hwang , Dae Won Kim , Min Jea Shin","doi":"10.1016/j.mcn.2024.103978","DOIUrl":"10.1016/j.mcn.2024.103978","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103978"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-09-07DOI: 10.1016/j.mcn.2024.103968
Junyou Gong , Xianghan Duan , Biyu Xiang , Lijun Qin , Jiejie Hu
Chronic migraine is a common central nervous system disorder characterized by recurrent, pulsating headaches. However, the extent and mechanisms of hypothalamic involvement in disease progression have not been thoroughly investigated. Herein, we created a chronic migraine mouse model using repeated intraperitoneal injections of nitroglycerin. We performed transcriptomic sequencing on the hypothalamus of mice with chronic migraine and control mice under normal physiological conditions, followed by differential gene set enrichment and functional analysis of the data. Additionally, we examined the intrinsic connection between chronic migraine and sleep disorders using transcriptomic sequencing data from sleep-deprived mice available in public databases. We identified 39 differentially expressed genes (DEGs) in the hypothalamus of a mouse model of chronic migraine. Functional analysis of DEGs revealed enrichment primarily in signaling transduction, immune-inflammatory responses, and the cellular microenvironment. A comparison of the transcriptomic data of sleep-deprived mice revealed two commonly expressed DEGs. Our findings indicate that the hypothalamic DEGs are primarily enriched in the PI3K/AKT/mTOR pathway and associated with the NF-κB/NLRP3/IL-1 β pathway activation to maintain the central sensitization of the chronic migraine. Chronic migraine-induced gene expression changes in the hypothalamus may help better understand the underlying mechanisms and identify therapeutic targets.
{"title":"Transcriptomic changes in the hypothalamus of mice with chronic migraine: Activation of pathways associated with neuropathic inflammation and central sensitization","authors":"Junyou Gong , Xianghan Duan , Biyu Xiang , Lijun Qin , Jiejie Hu","doi":"10.1016/j.mcn.2024.103968","DOIUrl":"10.1016/j.mcn.2024.103968","url":null,"abstract":"<div><p>Chronic migraine is a common central nervous system disorder characterized by recurrent, pulsating headaches. However, the extent and mechanisms of hypothalamic involvement in disease progression have not been thoroughly investigated. Herein, we created a chronic migraine mouse model using repeated intraperitoneal injections of nitroglycerin. We performed transcriptomic sequencing on the hypothalamus of mice with chronic migraine and control mice under normal physiological conditions, followed by differential gene set enrichment and functional analysis of the data. Additionally, we examined the intrinsic connection between chronic migraine and sleep disorders using transcriptomic sequencing data from sleep-deprived mice available in public databases. We identified 39 differentially expressed genes (DEGs) in the hypothalamus of a mouse model of chronic migraine. Functional analysis of DEGs revealed enrichment primarily in signaling transduction, immune-inflammatory responses, and the cellular microenvironment. A comparison of the transcriptomic data of sleep-deprived mice revealed two commonly expressed DEGs. Our findings indicate that the hypothalamic DEGs are primarily enriched in the PI3K/AKT/mTOR pathway and associated with the NF-κB/NLRP3/IL-1 β pathway activation to maintain the central sensitization of the chronic migraine. Chronic migraine-induced gene expression changes in the hypothalamus may help better understand the underlying mechanisms and identify therapeutic targets.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103968"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142169242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-11-22DOI: 10.1016/j.mcn.2024.103980
Zehua Tan , Ruixin Xia , Xin Zhao , Zile Yang, Haiying Liu, Wenting Wang
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication deficits, as well as restricted or repetitive behaviors or interests. Although the etiology of ASD remains unclear, there is abundant evidence suggesting that microglial dysfunction is likely to be a significant factor in the pathophysiology of ASD. Microglia, the primary innate immune cells in the central nervous system (CNS), play a crucial role in brain development and homeostasis. Recently, numerous studies have shown that microglia in ASD models display various abnormalities including morphology, function, cellular interactions, genetic and epigenetic factors, as well as the expression of receptors, transcription factors, and cytokines. They impact normal neural development through various mechanisms contributing to ASD, such as neuroinflammation, and alterations in synaptic formation and pruning. The focus of this review is on recent studies regarding microglial abnormalities in ASD and their effects on the onset and progression of ASD at both cellular and molecular levels. It can provide insight into the specific contribution of microglia to ASD pathogenesis and help in designing potential therapeutic and preventative strategies targeting microglia.
{"title":"Potential key pathophysiological participant and treatment target in autism spectrum disorder: Microglia","authors":"Zehua Tan , Ruixin Xia , Xin Zhao , Zile Yang, Haiying Liu, Wenting Wang","doi":"10.1016/j.mcn.2024.103980","DOIUrl":"10.1016/j.mcn.2024.103980","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication deficits, as well as restricted or repetitive behaviors or interests. Although the etiology of ASD remains unclear, there is abundant evidence suggesting that microglial dysfunction is likely to be a significant factor in the pathophysiology of ASD. Microglia, the primary innate immune cells in the central nervous system (CNS), play a crucial role in brain development and homeostasis. Recently, numerous studies have shown that microglia in ASD models display various abnormalities including morphology, function, cellular interactions, genetic and epigenetic factors, as well as the expression of receptors, transcription factors, and cytokines. They impact normal neural development through various mechanisms contributing to ASD, such as neuroinflammation, and alterations in synaptic formation and pruning. The focus of this review is on recent studies regarding microglial abnormalities in ASD and their effects on the onset and progression of ASD at both cellular and molecular levels. It can provide insight into the specific contribution of microglia to ASD pathogenesis and help in designing potential therapeutic and preventative strategies targeting microglia.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103980"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-20DOI: 10.1016/j.mcn.2024.103977
Mustafa C. Beker , Mehmet O. Altintas , Enes Dogan , Cigdem Bayraktaroglu , Buse Balaban , Aysenur Ozpinar , Nursena Sengun , Serdar Altunay , Ertugrul Kilic
Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.
{"title":"Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury","authors":"Mustafa C. Beker , Mehmet O. Altintas , Enes Dogan , Cigdem Bayraktaroglu , Buse Balaban , Aysenur Ozpinar , Nursena Sengun , Serdar Altunay , Ertugrul Kilic","doi":"10.1016/j.mcn.2024.103977","DOIUrl":"10.1016/j.mcn.2024.103977","url":null,"abstract":"<div><div>Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103977"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-11-22DOI: 10.1016/j.mcn.2024.103976
Mikaela M. Ceder, Kajsa A. Magnusson, Hannah M. Weman, Katharina Henriksson, Linn Andréasson, Teresa Lindström, Oskar Wiggins, Malin C. Lagerström
Glycine receptors are ligand-gated chloride-selective channels that control excitability in the central nervous system (CNS). Herein, we have investigated the mRNA expression of the glycine receptor alpha 1 (Glra1), alpha 2 (Glra2), alpha 4 (Glra4) and the beta (Glrb) subunits, in adult female and male mice.
Single-cell RNA sequencing data re-analysis of the Zeisel et al. (2018) dataset indicated widespread expression of Glra1, Glra2 and Glrb in the CNS, while only a few cells in the cortex, striatum, thalamus, midbrain and the spinal cord expressed Glra4. Highest occurrence of Glra1, Glra2 and Glrb were found in the brainstem. Moreover, Glra1 and Glrb were revealed to have the highest occurrences in the spinal cord of the investigated subunits. However, both Glra2 and Glrb had a more widespread expression in the CNS compared with Glra1 and Glra4. Bulk quantitative real-time-PCR (qRT-PCR) analysis revealed Glra1 expression in the hypothalamus, thalamus, brainstem and the spinal cord, and widespread, but low, Glra2 and Glrb expression in the CNS. Moreover, Glrb could be detected in a few visceral organs. Additionally, females and males were found to express Glra1, Glra2 and Glrb differently in certain brain areas such as the brainstem. Expression levels of Glra4 were too low to be detected using qRT-PCR. Lastly, RNAscope spatially validated the expression of Glra1, Glra2 and Glrb in the areas indicated by the single-cell and bulk analyses, and further revealed that Glra4 can be detected in the cortex, amygdala, hypothalamus, thalamus, brainstem, especially the cochlear nucleus, and in the spinal cord.
{"title":"The mRNA expression profile of glycine receptor subunits alpha 1, alpha 2, alpha 4 and beta in female and male mice","authors":"Mikaela M. Ceder, Kajsa A. Magnusson, Hannah M. Weman, Katharina Henriksson, Linn Andréasson, Teresa Lindström, Oskar Wiggins, Malin C. Lagerström","doi":"10.1016/j.mcn.2024.103976","DOIUrl":"10.1016/j.mcn.2024.103976","url":null,"abstract":"<div><div>Glycine receptors are ligand-gated chloride-selective channels that control excitability in the central nervous system (CNS). Herein, we have investigated the mRNA expression of the glycine receptor alpha 1 (<em>Glra1</em>), alpha 2 (<em>Glra2</em>), alpha 4 (<em>Glra4</em>) and the beta (<em>Glrb</em>) subunits, in adult female and male mice.</div><div>Single-cell RNA sequencing data re-analysis of the <span><span>Zeisel et al. (2018)</span></span> dataset indicated widespread expression of <em>Glra1</em>, <em>Glra2</em> and <em>Glrb</em> in the CNS, while only a few cells in the cortex, striatum, thalamus, midbrain and the spinal cord expressed <em>Glra4</em>. Highest occurrence of <em>Glra1</em>, <em>Glra2</em> and <em>Glrb</em> were found in the brainstem. Moreover, <em>Glra1</em> and <em>Glrb</em> were revealed to have the highest occurrences in the spinal cord of the investigated subunits. However, both <em>Glra2</em> and <em>Glrb</em> had a more widespread expression in the CNS compared with <em>Glra1</em> and <em>Glra4</em>. Bulk quantitative real-time-PCR (qRT-PCR) analysis revealed <em>Glra1</em> expression in the hypothalamus, thalamus, brainstem and the spinal cord, and widespread, but low, <em>Glra2</em> and <em>Glrb</em> expression in the CNS. Moreover, <em>Glrb</em> could be detected in a few visceral organs. Additionally, females and males were found to express <em>Glra1</em>, <em>Glra2</em> and <em>Glrb</em> differently in certain brain areas such as the brainstem. Expression levels of <em>Glra4</em> were too low to be detected using qRT-PCR. Lastly, RNAscope spatially validated the expression of <em>Glra1</em>, <em>Glra2</em> and <em>Glrb</em> in the areas indicated by the single-cell and bulk analyses, and further revealed that <em>Glra4</em> can be detected in the cortex, amygdala, hypothalamus, thalamus, brainstem, especially the cochlear nucleus, and in the spinal cord.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103976"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-05DOI: 10.1016/j.mcn.2024.103974
Nina Daniels, Aidan D. Bindoff, James C. Vickers, Anna E. King , Jessica M. Collins
Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.
{"title":"Vulnerability of neurofilament-expressing neurons in frontotemporal dementia","authors":"Nina Daniels, Aidan D. Bindoff, James C. Vickers, Anna E. King , Jessica M. Collins","doi":"10.1016/j.mcn.2024.103974","DOIUrl":"10.1016/j.mcn.2024.103974","url":null,"abstract":"<div><div>Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103974"},"PeriodicalIF":2.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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