Anastasia Schultz, Henar Albertos-Arranz, Xavier Sánchez Sáez, Jamie Morgan, Diane C. Darland, Alejandra Gonzalez-Duarte, Horacio Kaufmann, Carlos E. Mendoza-Santiesteban, Nicolás Cuenca, Frances Lefcort
Familial dysautonomia (FD) is a rare genetic neurodevelopmental and neurodegenerative disorder. In addition to the autonomic and peripheral sensory neuropathies that challenge patient survival, one of the most debilitating symptoms affecting patients' quality of life is progressive blindness resulting from the steady loss of retinal ganglion cells (RGCs). Within the FD community, there is a concerted effort to develop treatments to prevent the loss of RGCs. However, the mechanisms underlying the death of RGCs are not well understood. To study the mechanisms underlying RGC death, Pax6-cre;Elp1loxp/loxp male and female mice and postmortem retinal tissue from an FD patient were used to explore the neuronal and non-neuronal cellular pathology associated with the FD optic neuropathy. Neurons, astrocytes, microglia, Müller glia, and endothelial cells were investigated using a combination of histological analyses. We identified a novel disruption of cellular homeostasis and gliosis in the FD retina. Beginning shortly after birth and progressing with age, the FD retina is marked by astrogliosis and perturbations in microglia, which coincide with vascular remodeling. These changes begin before the onset of RGC death, suggesting alterations in the retinal neurovascular unit may contribute to and exacerbate RGC death. We reveal for the first time that the FD retina pathology includes reactive gliosis, increased microglial recruitment to the ganglion cell layer (GCL), disruptions in the deep and superficial vascular plexuses, and alterations in signaling pathways. These studies implicate the neurovascular unit as a disease-modifying target for therapeutic interventions in FD.
{"title":"Neuronal and glial cell alterations involved in the retinal degeneration of the familial dysautonomia optic neuropathy","authors":"Anastasia Schultz, Henar Albertos-Arranz, Xavier Sánchez Sáez, Jamie Morgan, Diane C. Darland, Alejandra Gonzalez-Duarte, Horacio Kaufmann, Carlos E. Mendoza-Santiesteban, Nicolás Cuenca, Frances Lefcort","doi":"10.1002/glia.24612","DOIUrl":"10.1002/glia.24612","url":null,"abstract":"<p>Familial dysautonomia (FD) is a rare genetic neurodevelopmental and neurodegenerative disorder. In addition to the autonomic and peripheral sensory neuropathies that challenge patient survival, one of the most debilitating symptoms affecting patients' quality of life is progressive blindness resulting from the steady loss of retinal ganglion cells (RGCs). Within the FD community, there is a concerted effort to develop treatments to prevent the loss of RGCs. However, the mechanisms underlying the death of RGCs are not well understood. To study the mechanisms underlying RGC death, <i>Pax6-cre;Elp1</i><sup><i>loxp/loxp</i></sup> male and female mice and postmortem retinal tissue from an FD patient were used to explore the neuronal and non-neuronal cellular pathology associated with the FD optic neuropathy. Neurons, astrocytes, microglia, Müller glia, and endothelial cells were investigated using a combination of histological analyses. We identified a novel disruption of cellular homeostasis and gliosis in the FD retina. Beginning shortly after birth and progressing with age, the FD retina is marked by astrogliosis and perturbations in microglia, which coincide with vascular remodeling. These changes begin before the onset of RGC death, suggesting alterations in the retinal neurovascular unit may contribute to and exacerbate RGC death. We reveal for the first time that the FD retina pathology includes reactive gliosis, increased microglial recruitment to the ganglion cell layer (GCL), disruptions in the deep and superficial vascular plexuses, and alterations in signaling pathways. These studies implicate the neurovascular unit as a disease-modifying target for therapeutic interventions in FD.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2268-2294"},"PeriodicalIF":5.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24612","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124371","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}
Jónvá Hentze, Jonas Folke, Susana Aznar, Pia Nyeng, Tomasz Brudek, Christian Hansen
DNAJB6 is a suppressor of α-synuclein aggregation in vivo and in vitro. DNAJB6 is strongly expressed in the brain, and its overall protein expression is altered in neurodegenerative conditions such as Parkinson's Disease (PD) and Multiple System Atrophy (MSA). These two diseases are characterized by accumulation of aggregated α-synuclein in neurons and oligodendrocytes, respectively. To further explore this, we employed post-mortem normal human brain material to investigate the regional and cell type specific protein expression of DNAJB6. We found that the DNAJB6 protein is ubiquitously expressed across various regions of the brain. Notably, we demonstrate for the first time that DNAJB6 is present in nearly half (41%–53%) of the oligodendrocyte population and in the majority (68%–80%) of neurons. However, DNAJB6 was only sparsely present in other cell types such as astrocytes and microglia. Given that α-synuclein aggregation in oligodendrocytes is a hallmark of MSA, we investigated DNAJB6 presence in MSA brains compared to control brains. We found no significant difference in the percentage of oligodendrocytes where DNAJB6 was present in MSA brains relative to control brains. In conclusion, our results reveal an expression of the DNAJB6 protein across various regions of the human brain, and that DNAJB6 is almost exclusively present in neurons and oligodendrocytes. Since prior studies have shown that PD and MSA brains have altered levels of DNAJB6 relative to control brains, DNAJB6 may be an interesting target for drug development.
{"title":"DNAJB6 is expressed in neurons and oligodendrocytes of the human brain","authors":"Jónvá Hentze, Jonas Folke, Susana Aznar, Pia Nyeng, Tomasz Brudek, Christian Hansen","doi":"10.1002/glia.24615","DOIUrl":"10.1002/glia.24615","url":null,"abstract":"<p>DNAJB6 is a suppressor of α-synuclein aggregation <i>in vivo</i> and <i>in vitro</i>. DNAJB6 is strongly expressed in the brain, and its overall protein expression is altered in neurodegenerative conditions such as Parkinson's Disease (PD) and Multiple System Atrophy (MSA). These two diseases are characterized by accumulation of aggregated α-synuclein in neurons and oligodendrocytes, respectively. To further explore this, we employed <i>post-mortem</i> normal human brain material to investigate the regional and cell type specific protein expression of DNAJB6. We found that the DNAJB6 protein is ubiquitously expressed across various regions of the brain. Notably, we demonstrate for the first time that DNAJB6 is present in nearly half (41%–53%) of the oligodendrocyte population and in the majority (68%–80%) of neurons. However, DNAJB6 was only sparsely present in other cell types such as astrocytes and microglia. Given that α-synuclein aggregation in oligodendrocytes is a hallmark of MSA, we investigated DNAJB6 presence in MSA brains compared to control brains. We found no significant difference in the percentage of oligodendrocytes where DNAJB6 was present in MSA brains relative to control brains. In conclusion, our results reveal an expression of the DNAJB6 protein across various regions of the human brain, and that DNAJB6 is almost exclusively present in neurons and oligodendrocytes. Since prior studies have shown that PD and MSA brains have altered levels of DNAJB6 relative to control brains, DNAJB6 may be an interesting target for drug development.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2313-2326"},"PeriodicalIF":5.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124369","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}
Emma R. Wilson, Gustavo Della-Flora Nunes, Shichen Shen, Seth Moore, Joseph Gawron, Jessica Maxwell, Umair Syed, Edward Hurley, Meghana Lanka, Jun Qu, Laurent Désaubry, Lawrence Wrabetz, Yannick Poitelon, M. Laura Feltri
Schwann cells are critical for the proper development and function of the peripheral nervous system (PNS), where they form a collaborative relationship with axons. Past studies highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this, showing that drug-mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (Phb2) in vivo results in severe defects in radial sorting and myelination. We show in vivo that Phb2-null Schwann cells cannot effectively proliferate and the transcription factors EGR2 (KROX20), POU3F1 (OCT6), and POU3F2 (BRN2), necessary for proper Schwann cell maturation, are dysregulated. Schwann cell-specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the developmental defect seen in mice lacking Schwann cell Phb2. Finally, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on neuronal signals, and thus are potential mediators of PHB2-associated developmental defects. This work develops our understanding of Schwann cell biology, revealing that Phb2 may modulate the timely expression of transcription factors necessary for proper PNS development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell.
{"title":"Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination","authors":"Emma R. Wilson, Gustavo Della-Flora Nunes, Shichen Shen, Seth Moore, Joseph Gawron, Jessica Maxwell, Umair Syed, Edward Hurley, Meghana Lanka, Jun Qu, Laurent Désaubry, Lawrence Wrabetz, Yannick Poitelon, M. Laura Feltri","doi":"10.1002/glia.24610","DOIUrl":"10.1002/glia.24610","url":null,"abstract":"<p>Schwann cells are critical for the proper development and function of the peripheral nervous system (PNS), where they form a collaborative relationship with axons. Past studies highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this, showing that drug-mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (<i>Phb2</i>) in vivo results in severe defects in radial sorting and myelination. We show in vivo that <i>Phb2</i>-null Schwann cells cannot effectively proliferate and the transcription factors EGR2 (KROX20), POU3F1 (OCT6), and POU3F2 (BRN2), necessary for proper Schwann cell maturation, are dysregulated. Schwann cell-specific deletion of <i>Jun</i>, a transcription factor associated with negative regulation of myelination, confers partial rescue of the developmental defect seen in mice lacking Schwann cell <i>Phb2</i>. Finally, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on neuronal signals, and thus are potential mediators of PHB2-associated developmental defects. This work develops our understanding of Schwann cell biology, revealing that <i>Phb2</i> may modulate the timely expression of transcription factors necessary for proper PNS development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2247-2267"},"PeriodicalIF":5.4,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102646","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}
Nira Hernández-Martín, María Gómez Martínez, Pablo Bascuñana, Rubén Fernández de la Rosa, Luis García-García, Francisca Gómez, Maite Solas, Eduardo D. Martín, Miguel A. Pozo
Astrocytes play a multifaceted role regulating brain glucose metabolism, ion homeostasis, neurotransmitters clearance, and water dynamics being essential in supporting synaptic function. Under different pathological conditions such as brain stroke, epilepsy, and neurodegenerative disorders, excitotoxicity plays a crucial role, however, the contribution of astrocytic activity in protecting neurons from excitotoxicity-induced damage is yet to be fully understood. In this work, we evaluated the effect of astrocytic activation by Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on brain glucose metabolism in wild-type (WT) mice, and we investigated the effects of sustained astrocyte activation following an insult induced by intrahippocampal (iHPC) kainic acid (KA) injection using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) positron emission tomography (PET) imaging, along with behavioral test, nuclear magnetic resonance (NMR) spectroscopy and histochemistry. Astrocytic Ca2+ activation increased the 18F-FDG uptake, but this effect was not found when the study was performed in knock out mice for type-2 inositol 1,4,5-trisphosphate receptor (Ip3r2−/−) nor in floxed mice to abolish glucose transporter 1 (GLUT1) expression in hippocampal astrocytes (GLUT1ΔGFAP). Sustained astrocyte activation after KA injection reversed the brain glucose hypometabolism, restored hippocampal function, prevented neuronal death, and increased hippocampal GABA levels. The findings of our study indicate that astrocytic GLUT1 function is crucial for regulating brain glucose metabolism. Astrocytic Ca2+ activation has been shown to promote adaptive changes that significantly contribute to mitigating the effects of KA-induced damage. This evidence suggests a protective role of activated astrocytes against KA-induced excitotoxicity.
{"title":"Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus","authors":"Nira Hernández-Martín, María Gómez Martínez, Pablo Bascuñana, Rubén Fernández de la Rosa, Luis García-García, Francisca Gómez, Maite Solas, Eduardo D. Martín, Miguel A. Pozo","doi":"10.1002/glia.24607","DOIUrl":"10.1002/glia.24607","url":null,"abstract":"<p>Astrocytes play a multifaceted role regulating brain glucose metabolism, ion homeostasis, neurotransmitters clearance, and water dynamics being essential in supporting synaptic function. Under different pathological conditions such as brain stroke, epilepsy, and neurodegenerative disorders, excitotoxicity plays a crucial role, however, the contribution of astrocytic activity in protecting neurons from excitotoxicity-induced damage is yet to be fully understood. In this work, we evaluated the effect of astrocytic activation by Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on brain glucose metabolism in wild-type (WT) mice, and we investigated the effects of sustained astrocyte activation following an insult induced by intrahippocampal (iHPC) kainic acid (KA) injection using 2-deoxy-2-[<sup>18</sup>F]-fluoro-D-glucose (<sup>18</sup>F-FDG) positron emission tomography (PET) imaging, along with behavioral test, nuclear magnetic resonance (NMR) spectroscopy and histochemistry. Astrocytic Ca<sup>2+</sup> activation increased the <sup>18</sup>F-FDG uptake, but this effect was not found when the study was performed in <i>knock out</i> mice for type-2 inositol 1,4,5-trisphosphate receptor (Ip3r2<sup>−/−</sup>) nor in <i>floxed</i> mice to abolish glucose transporter 1 (GLUT1) expression in hippocampal astrocytes (GLUT1<sup>ΔGFAP</sup>). Sustained astrocyte activation after KA injection reversed the brain glucose hypometabolism, restored hippocampal function, prevented neuronal death, and increased hippocampal GABA levels. The findings of our study indicate that astrocytic GLUT1 function is crucial for regulating brain glucose metabolism. Astrocytic Ca<sup>2+</sup> activation has been shown to promote adaptive changes that significantly contribute to mitigating the effects of KA-induced damage. This evidence suggests a protective role of activated astrocytes against KA-induced excitotoxicity.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2217-2230"},"PeriodicalIF":5.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24607","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071560","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}
Na+-K+-2Cl− cotransporter-1 (NKCC1) is present in brain cells, including astrocytes. The expression of astrocytic NKCC1 increases in the acute phase of traumatic brain injury (TBI), which induces brain edema. Endothelin-1 (ET-1) is a factor that induces brain edema and regulates the expression of several pathology-related genes in astrocytes. In the present study, we investigated the effect of ET-1 on NKCC1 expression in astrocytes. ET-1 (100 nM)-treated cultured astrocytes showed increased NKCC1 mRNA and protein levels. The effect of ET-1 on NKCC1 expression in cultured astrocytes was reduced by BQ788 (1 μM), an ETB antagonist, but not by FR139317 (1 μM), an ETA antagonist. The involvement of ET-1 in NKCC1 expression in TBI was examined using a fluid percussion injury (FPI) mouse model that replicates the pathology of TBI with high reproducibility. Administration of BQ788 (15 nmol/day) decreased FPI-induced expressions of NKCC1 mRNA and protein, accompanied with a reduction of astrocytic activation. FPI-induced brain edema was attenuated by BQ788 and NKCC1 inhibitors (azosemide and bumetanide). ET-1-treated cultured astrocytes showed increased mRNA and protein expression of hypoxia-inducible factor-1α (HIF1α). Immunohistochemical observations of mouse cerebrum after FPI showed co-localization of HIF1α with GFAP-positive astrocytes. Increased HIF1α expression in the TBI model was reversed by BQ788. FM19G11 (an HIF inhibitor, 1 μM) and HIF1α siRNA suppressed ET-induced increase in NKCC1 expression in cultured astrocytes. These results indicate that ET-1 increases NKCC1 expression in astrocytes through the activation of HIF1α.
{"title":"Endothelin-1 increases Na+-K+-2Cl− cotransporter-1 expression in cultured astrocytes and in traumatic brain injury model: An involvement of HIF1α activation","authors":"Yutaka Koyama, Yasuhiro Hamada, Yura Fukui, Nami Hosogi, Rina Fujimoto, Shigeru Hishinuma, Yasuhiro Ogawa, Kenta Takahashi, Yasuhiko Izumi, Shotaro Michinaga","doi":"10.1002/glia.24609","DOIUrl":"10.1002/glia.24609","url":null,"abstract":"<p>Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter-1 (NKCC1) is present in brain cells, including astrocytes. The expression of astrocytic NKCC1 increases in the acute phase of traumatic brain injury (TBI), which induces brain edema. Endothelin-1 (ET-1) is a factor that induces brain edema and regulates the expression of several pathology-related genes in astrocytes. In the present study, we investigated the effect of ET-1 on NKCC1 expression in astrocytes. ET-1 (100 nM)-treated cultured astrocytes showed increased NKCC1 mRNA and protein levels. The effect of ET-1 on NKCC1 expression in cultured astrocytes was reduced by BQ788 (1 μM), an ET<sub>B</sub> antagonist, but not by FR139317 (1 μM), an ET<sub>A</sub> antagonist. The involvement of ET-1 in NKCC1 expression in TBI was examined using a fluid percussion injury (FPI) mouse model that replicates the pathology of TBI with high reproducibility. Administration of BQ788 (15 nmol/day) decreased FPI-induced expressions of NKCC1 mRNA and protein, accompanied with a reduction of astrocytic activation. FPI-induced brain edema was attenuated by BQ788 and NKCC1 inhibitors (azosemide and bumetanide). ET-1-treated cultured astrocytes showed increased mRNA and protein expression of hypoxia-inducible factor-1α (HIF1α). Immunohistochemical observations of mouse cerebrum after FPI showed co-localization of HIF1α with GFAP-positive astrocytes. Increased HIF1α expression in the TBI model was reversed by BQ788. FM19G11 (an HIF inhibitor, 1 μM) and HIF1α siRNA suppressed ET-induced increase in NKCC1 expression in cultured astrocytes. These results indicate that ET-1 increases NKCC1 expression in astrocytes through the activation of HIF1α.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2231-2246"},"PeriodicalIF":5.4,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007950","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}
Bianca Nicole Santos Paes Medina, Taynan Motta Portal, Carlos Augusto Borges de Andrade Gomes, Rodrigo Nunes-da-Fonseca, Silvana Allodi, Cintia Monteiro-de-Barros
The mechanisms underlying regeneration of the central nervous system (CNS) following lesions have been studied extensively in both vertebrate and invertebrate models. To shed light on regeneration, ascidians, a sister group of vertebrates and with remarkable ability to regenerate their brains, constitute an appropriate model system. Glial cells have been implicated in regeneration in vertebrates; however, their role in the adult ascidian CNS regeneration is unknown. A model of degeneration and regeneration using the neurotoxin 3-acetylpyridine (3AP) in the brain of the ascidian Styela plicata was used to identify astrocyte-like cells and investigate their role. We studied the CNS of control ascidians (injected with artificial sea water) and of ascidians whose CNS was regenerating (1 and 10 days after the injection with 3AP). Our results show that the mRNA of the ortholog of glutamine synthetase (GS), a glial-cell marker in vertebrates, is increased during the early stages of regeneration. Confirming the identity of GS, the protein was identified via immunostaining in a cell population during the same regeneration stage. Last, a single ortholog of GS (GSII) is present in ascidian and amphioxus genomes, while two types exist in fungi, some invertebrates, and vertebrates, suggesting that ascidians have lost the GSI type. Taken together, our findings revealed that a cell population expressing glial-cell markers may play a role in regeneration in adult ascidians. This is the first report of astrocyte-like cells in the adult ascidian CNS, and contributes to understanding of the evolution of glial cells among metazoans.
{"title":"Identification of astrocyte-like cells in an adult ascidian during regeneration of the central nervous system","authors":"Bianca Nicole Santos Paes Medina, Taynan Motta Portal, Carlos Augusto Borges de Andrade Gomes, Rodrigo Nunes-da-Fonseca, Silvana Allodi, Cintia Monteiro-de-Barros","doi":"10.1002/glia.24605","DOIUrl":"10.1002/glia.24605","url":null,"abstract":"<p>The mechanisms underlying regeneration of the central nervous system (CNS) following lesions have been studied extensively in both vertebrate and invertebrate models. To shed light on regeneration, ascidians, a sister group of vertebrates and with remarkable ability to regenerate their brains, constitute an appropriate model system. Glial cells have been implicated in regeneration in vertebrates; however, their role in the adult ascidian CNS regeneration is unknown. A model of degeneration and regeneration using the neurotoxin 3-acetylpyridine (3AP) in the brain of the ascidian <i>Styela plicata</i> was used to identify astrocyte-like cells and investigate their role. We studied the CNS of control ascidians (injected with artificial sea water) and of ascidians whose CNS was regenerating (1 and 10 days after the injection with 3AP). Our results show that the mRNA of the ortholog of glutamine synthetase (GS), a glial-cell marker in vertebrates, is increased during the early stages of regeneration. Confirming the identity of GS, the protein was identified via immunostaining in a cell population during the same regeneration stage. Last, a single ortholog of GS (GSII) is present in ascidian and amphioxus genomes, while two types exist in fungi, some invertebrates, and vertebrates, suggesting that ascidians have lost the GSI type. Taken together, our findings revealed that a cell population expressing glial-cell markers may play a role in regeneration in adult ascidians. This is the first report of astrocyte-like cells in the adult ascidian CNS, and contributes to understanding of the evolution of glial cells among metazoans.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2190-2200"},"PeriodicalIF":5.4,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994845","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}
Sonia Cabeza-Fernández, Rubí Hernández-Rojas, Angeles Casillas-Bajo, Nikiben Patel, Alerie G. de la Fuente, Hugo Cabedo, Jose A. Gomez-Sanchez
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1G93A mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1G93A mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.
肌萎缩侧索硬化症是一种以运动神经元死亡和远端轴突病变为特征的破坏性神经退行性疾病。尽管该病临床症状严重,对患者及其家庭影响深远,但有关其发病机制的许多问题仍不清楚,包括许旺细胞和轴突胶质细胞信号传导在疾病进展中的作用。轴突损伤后,JUN转录因子的上调会促进许旺细胞重编程为修复表型,从而有利于轴突再生和神经元存活。为了研究肌萎缩性脊髓侧索硬化症中修复许旺细胞对运动神经元存活的潜在作用,我们生成了一个小鼠品系,在该病的小鼠模型 SOD1G93A 突变体的许旺细胞中过度表达 JUN。然后,我们通过评估这些小鼠的存活率、运动表现以及外周神经和脊髓组织学来探索疾病的进展。我们发现,SOD1G93A 小鼠过表达许旺细胞 JUN 既不能防止轴突变性,也不能防止运动神经元死亡。相反,它会诱导中型和大型轴突的部分脱髓鞘,使运动表现恶化,并导致更具侵袭性的疾病表型。
{"title":"Schwann cell JUN expression worsens motor performance in an amyotrophic lateral sclerosis mouse model","authors":"Sonia Cabeza-Fernández, Rubí Hernández-Rojas, Angeles Casillas-Bajo, Nikiben Patel, Alerie G. de la Fuente, Hugo Cabedo, Jose A. Gomez-Sanchez","doi":"10.1002/glia.24604","DOIUrl":"10.1002/glia.24604","url":null,"abstract":"<p>Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1<sup>G93A</sup> mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1<sup>G93A</sup> mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2178-2189"},"PeriodicalIF":5.4,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24604","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986996","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}
Jens V. Andersen, Helle S. Waagepetersen, Lasse K. Bak
{"title":"In Memoriam: Arne Schousboe 1944–2024","authors":"Jens V. Andersen, Helle S. Waagepetersen, Lasse K. Bak","doi":"10.1002/glia.24608","DOIUrl":"10.1002/glia.24608","url":null,"abstract":"","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2357-2359"},"PeriodicalIF":5.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981336","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}
Elisa Degl'Innocenti, Tino Emanuele Poloni, Valentina Medici, Francesco Olimpico, Francesco Finamore, Xhulja Profka, Karouna Bascarane, Castrese Morrone, Aldo Pastore, Carole Escartin, Liam A. McDonnell, Maria Teresa Dell'Anno
Astrogliosis is a condition shared by acute and chronic neurological diseases and includes morphological, proteomic, and functional rearrangements of astroglia. In Alzheimer's disease (AD), reactive astrocytes frame amyloid deposits and exhibit structural changes associated with the overexpression of specific proteins, mostly belonging to intermediate filaments. At a functional level, amyloid beta triggers dysfunctional calcium signaling in astrocytes, which contributes to the maintenance of chronic neuroinflammation. Therefore, the identification of intracellular players that participate in astrocyte calcium signaling can help unveil the mechanisms underlying astrocyte reactivity and loss of function in AD. We have recently identified the calcium-binding protein centrin-2 (CETN2) as a novel astrocyte marker in the human brain and, in order to determine whether astrocytic CETN2 expression and distribution could be affected by neurodegenerative conditions, we examined its pattern in control and sporadic AD patients. By immunoblot, immunohistochemistry, and targeted-mass spectrometry, we report a positive correlation between entorhinal CETN2 immunoreactivity and neurocognitive impairment, along with the abundance of amyloid depositions and neurofibrillary tangles, thus highlighting a linear relationship between CETN2 expression and AD progression. CETN2-positive astrocytes were dispersed in the entorhinal cortex with a clustered pattern and colocalized with reactive glia markers STAT3, NFATc3, and YKL-40, indicating a human-specific role in AD-induced astrogliosis. Collectively, our data provide the first evidence that CETN2 is part of the astrocytic calcium toolkit undergoing rearrangements in AD and adds CETN2 to the list of proteins that could play a role in disease evolution.
星形胶质细胞增多症是急性和慢性神经系统疾病的共同症状,包括星形胶质细胞的形态学、蛋白质组和功能重排。在阿尔茨海默病(AD)中,反应性星形胶质细胞会形成淀粉样沉积物,并表现出与特定蛋白质(大多属于中间丝)过度表达相关的结构变化。在功能层面上,淀粉样蛋白 beta 会引发星形胶质细胞中的钙信号功能失调,从而导致慢性神经炎症的维持。因此,鉴定参与星形胶质细胞钙信号转导的细胞内参与者有助于揭示AD中星形胶质细胞反应性和功能丧失的内在机制。为了确定星形胶质细胞 CETN2 的表达和分布是否会受到神经退行性疾病的影响,我们研究了其在对照组和散发性 AD 患者中的表达模式。通过免疫印迹、免疫组织化学和靶向质谱分析,我们发现内侧星形胶质细胞 CETN2 免疫活性与神经认知功能障碍以及淀粉样沉积和神经纤维缠结的丰度呈正相关,从而凸显了 CETN2 表达与 AD 进展之间的线性关系。CETN2阳性星形胶质细胞以聚集模式分散在内侧皮层,并与反应性胶质细胞标记物STAT3、NFATc3和YKL-40共聚焦,表明其在AD诱导的星形胶质细胞增生中具有人类特异性作用。总之,我们的数据首次证明了 CETN2 是 AD 中发生重排的星形胶质细胞钙工具箱的一部分,并将 CETN2 加入了可能在疾病演变中发挥作用的蛋白质列表。
{"title":"Astrocytic centrin-2 expression in entorhinal cortex correlates with Alzheimer's disease severity","authors":"Elisa Degl'Innocenti, Tino Emanuele Poloni, Valentina Medici, Francesco Olimpico, Francesco Finamore, Xhulja Profka, Karouna Bascarane, Castrese Morrone, Aldo Pastore, Carole Escartin, Liam A. McDonnell, Maria Teresa Dell'Anno","doi":"10.1002/glia.24603","DOIUrl":"10.1002/glia.24603","url":null,"abstract":"<p>Astrogliosis is a condition shared by acute and chronic neurological diseases and includes morphological, proteomic, and functional rearrangements of astroglia. In Alzheimer's disease (AD), reactive astrocytes frame amyloid deposits and exhibit structural changes associated with the overexpression of specific proteins, mostly belonging to intermediate filaments. At a functional level, amyloid beta triggers dysfunctional calcium signaling in astrocytes, which contributes to the maintenance of chronic neuroinflammation. Therefore, the identification of intracellular players that participate in astrocyte calcium signaling can help unveil the mechanisms underlying astrocyte reactivity and loss of function in AD. We have recently identified the calcium-binding protein centrin-2 (CETN2) as a novel astrocyte marker in the human brain and, in order to determine whether astrocytic CETN2 expression and distribution could be affected by neurodegenerative conditions, we examined its pattern in control and sporadic AD patients. By immunoblot, immunohistochemistry, and targeted-mass spectrometry, we report a positive correlation between entorhinal CETN2 immunoreactivity and neurocognitive impairment, along with the abundance of amyloid depositions and neurofibrillary tangles, thus highlighting a linear relationship between CETN2 expression and AD progression. CETN2-positive astrocytes were dispersed in the entorhinal cortex with a clustered pattern and colocalized with reactive glia markers STAT3, NFATc3, and YKL-40, indicating a human-specific role in AD-induced astrogliosis. Collectively, our data provide the first evidence that CETN2 is part of the astrocytic calcium toolkit undergoing rearrangements in AD and adds CETN2 to the list of proteins that could play a role in disease evolution.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 12","pages":"2158-2177"},"PeriodicalIF":5.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24603","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981335","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}
Cover Illustration: 3D remodeling of reprogrammed non-myelinated Schwann cells and their associated sympathetic axons in metaplastic pancreatic lesions compared to adjacent tissue. 3D visualization of a cleared pancreatic section from a mouse with chronic pancreatitis. The transparent purple volume encompassed a metaplastic lesion with increased density of Schwann cells (in red) and sympathetic axons (in green), while the blue volume represents adjacent tissue with minimal metaplastic and neural changes. Schwann cells were labeled with anti-GFRA3, sympathetic axons with anti-TH and metaplastic cells with anti-CK19, in cyan. (See Chauvet, S., et al, https://doi.org/10.1002/glia.24586)