Astrocytes in CNS Disorders

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 43544

Special Issue Editors


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Guest Editor
Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
Interests: regulation of GFAP expression; GFAP function; role of GFAP in Alexander disease

E-Mail Website
Guest Editor
International Translational Neuroscience Research Institute, Zhejiang Chinese Medical University, Hangzhou 310053, China
Interests: gliotransmission; glutamate; astrocytes; glioblastoma multiforme
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Special Issue Information

Dear Colleagues,

Over the past 30 years, astrocytes have emerged from a supporting role to co-starring with neurons and oligodendrocytes as players in CNS disorders. The number of reviews describing the involvement of astrocytes in neurodegenerative disorders published in 2021 equaled the total number for the 18 years from 1990 through 2007. Dysfunction of astrocytes is now implicated in disorders once thought to be solely of neuronal origin, such as epilepsy, amyotrophic lateral sclerosis, and depression. It is also implicated in disorders previously ascribed solely to oligodendrocytes, such as multiple sclerosis, vanishing white matter disease, and megalencephalic leukoencephalopathy with subcortical cysts. In some instances, the disease cause is a defect originating in astrocytes. The first and perhaps most definitive example is Alexander disease, in which coding mutations in the GFAP gene can cause massive dysmyelination and perturb multiple neuronal circuits. In other instances, induced disruption of normal astrocyte functions such as glutamate or potassium transport exacerbate the disease process. The purpose of this Special Issue is to illustrate the broad-ranging involvement of astrocytes in CNS disorders. Understanding their role in a variety of CNS disorders will be informative both for revealing normal interactions between astrocytes and other CNS cell types, and for identifying therapeutic targets.

Prof. Dr. Michael Brenner
Prof. Dr. Vladimir Parpura
Guest Editors

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Keywords

  • astrocytes
  • CNS disease
  • neurodegeneration
  • neuroprotection
  • novel therapeutic targets

Published Papers (22 papers)

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18 pages, 2437 KiB  
Article
Chemically Functionalized Single-Walled Carbon Nanotubes Prevent the Reduction in Plasmalemmal Glutamate Transporter EAAT1 Expression in, and Increase the Release of Selected Cytokines from, Stretch-Injured Astrocytes in Vitro
by Nika Gržeta Krpan, Anja Harej Hrkać, Tamara Janković, Petra Dolenec, Elena Bekyarova, Vladimir Parpura and Kristina Pilipović
Cells 2024, 13(3), 225; https://doi.org/10.3390/cells13030225 - 25 Jan 2024
Viewed by 706
Abstract
We tested the effects of water-soluble single-walled carbon nanotubes, chemically functionalized with polyethylene glycol (SWCNT-PEG), on primary mouse astrocytes exposed to a severe in vitro simulated traumatic brain injury (TBI). The application of SWCNT-PEG in the culture media of injured astrocytes did not [...] Read more.
We tested the effects of water-soluble single-walled carbon nanotubes, chemically functionalized with polyethylene glycol (SWCNT-PEG), on primary mouse astrocytes exposed to a severe in vitro simulated traumatic brain injury (TBI). The application of SWCNT-PEG in the culture media of injured astrocytes did not affect cell damage levels, when compared to those obtained from injured, functionalization agent (PEG)-treated cells. Furthermore, SWCNT-PEG did not change the levels of oxidatively damaged proteins in astrocytes. However, this nanomaterial prevented the reduction in plasmalemmal glutamate transporter EAAT1 expression caused by the injury, rendering the level of EAAT1 on par with that of control, uninjured PEG-treated astrocytes; in parallel, there was no significant change in the levels of GFAP. Additionally, SWCNT-PEG increased the release of selected cytokines that are generally considered to be involved in recovery processes following injuries. As a loss of EAATs has been implicated as a culprit in the suffering of human patients from TBI, the application of SWCNT-PEG could have valuable effects at the injury site, by preventing the loss of astrocytic EAAT1 and consequently allowing for a much-needed uptake of glutamate from the extracellular space, the accumulation of which leads to unwanted excitotoxicity. Additional potential therapeutic benefits could be reaped from the fact that SWCNT-PEG stimulated the release of selected cytokines from injured astrocytes, which would promote recovery after injury and thus counteract the excess of proinflammatory cytokines present in TBI. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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24 pages, 19095 KiB  
Article
The Matrix Receptor CD44 Is Present in Astrocytes throughout the Human Central Nervous System and Accumulates in Hypoxia and Seizures
by Osama Al-Dalahmah, Alexander A. Sosunov, Yu Sun, Yang Liu, Nacoya Madden, E. Sander Connolly, Carol M. Troy, Guy M. McKhann II and James E. Goldman
Cells 2024, 13(2), 129; https://doi.org/10.3390/cells13020129 - 10 Jan 2024
Viewed by 953
Abstract
In the mammalian isocortex, CD44, a cell surface receptor for extracellular matrix molecules, is present in pial-based and fibrous astrocytes of white matter but not in protoplasmic astrocytes. In the hominid isocortex, CD44+ astrocytes comprise the subpial “interlaminar” astrocytes, sending long processes into [...] Read more.
In the mammalian isocortex, CD44, a cell surface receptor for extracellular matrix molecules, is present in pial-based and fibrous astrocytes of white matter but not in protoplasmic astrocytes. In the hominid isocortex, CD44+ astrocytes comprise the subpial “interlaminar” astrocytes, sending long processes into the cortex. The hippocampus also contains similar astrocytes. We have examined all levels of the human central nervous system and found CD44+ astrocytes in every region. Astrocytes in white matter and astrocytes that interact with large blood vessels but not with capillaries in gray matter are CD44+, the latter extending long processes into the parenchyma. Motor neurons in the brainstem and spinal cord, such as oculomotor, facial, hypoglossal, and in the anterior horn of the spinal cord, are surrounded by CD44+ processes, contrasting with neurons in the cortex, basal ganglia, and thalamus. We found CD44+ processes that intercalate between ependymal cells to reach the ventricle. We also found CD44+ astrocytes in the molecular layer of the cerebellar cortex. Protoplasmic astrocytes, which do not normally contain CD44, acquire it in pathologies like hypoxia and seizures. The pervasive and inducible expression of CD44 in astrocytes is a novel finding that lays the foundations for functional studies into the significance of CD44 in health and disease. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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25 pages, 2624 KiB  
Article
Inward Operation of Sodium-Bicarbonate Cotransporter 1 Promotes Astrocytic Na+ Loading and Loss of ATP in Mouse Neocortex during Brief Chemical Ischemia
by Katharina Everaerts, Pawan Thapaliya, Nils Pape, Simone Durry, Sara Eitelmann, Eleni Roussa, Ghanim Ullah and Christine R. Rose
Cells 2023, 12(23), 2675; https://doi.org/10.3390/cells12232675 - 21 Nov 2023
Cited by 2 | Viewed by 1600
Abstract
Ischemic conditions cause an increase in the sodium concentration of astrocytes, driving the breakdown of ionic homeostasis and exacerbating cellular damage. Astrocytes express high levels of the electrogenic sodium-bicarbonate cotransporter1 (NBCe1), which couples intracellular Na+ homeostasis to regulation of pH and operates [...] Read more.
Ischemic conditions cause an increase in the sodium concentration of astrocytes, driving the breakdown of ionic homeostasis and exacerbating cellular damage. Astrocytes express high levels of the electrogenic sodium-bicarbonate cotransporter1 (NBCe1), which couples intracellular Na+ homeostasis to regulation of pH and operates close to its reversal potential under physiological conditions. Here, we analyzed its mode of operation during transient energy deprivation via imaging astrocytic pH, Na+, and ATP in organotypic slice cultures of the mouse neocortex, complemented with patch-clamp and ion-selective microelectrode recordings and computational modeling. We found that a 2 min period of metabolic failure resulted in a transient acidosis accompanied by a Na+ increase in astrocytes. Inhibition of NBCe1 increased the acidosis while decreasing the Na+ load. Similar results were obtained when comparing ion changes in wild-type and Nbce1-deficient mice. Mathematical modeling replicated these findings and further predicted that NBCe1 activation contributes to the loss of cellular ATP under ischemic conditions, a result confirmed experimentally using FRET-based imaging of ATP. Altogether, our data demonstrate that transient energy failure stimulates the inward operation of NBCe1 in astrocytes. This causes a significant amelioration of ischemia-induced astrocytic acidification, albeit at the expense of increased Na+ influx and a decline in cellular ATP. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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20 pages, 4482 KiB  
Article
Astrocytes in the Optic Nerve Are Heterogeneous in Their Reactivity to Glaucomatous Injury
by Ying Zhu, Rui Wang, Anthony C. Pappas, Philip Seifert, Andrej Savol, Ruslan I. Sadreyev, Daniel Sun and Tatjana C. Jakobs
Cells 2023, 12(17), 2131; https://doi.org/10.3390/cells12172131 - 23 Aug 2023
Cited by 3 | Viewed by 1250
Abstract
The optic nerve head is thought to be the site of initial injury to retinal ganglion cell injury in glaucoma. In the initial segment of the optic nerve directly behind the globe, the ganglion cell axons are unmyelinated and come into direct contact [...] Read more.
The optic nerve head is thought to be the site of initial injury to retinal ganglion cell injury in glaucoma. In the initial segment of the optic nerve directly behind the globe, the ganglion cell axons are unmyelinated and come into direct contact to astrocytes, suggesting that astrocytes may play a role in the pathology of glaucoma. As in other parts of the CNS, optic nerve head astrocytes respond to injury by characteristic changes in cell morphology and gene expression profile. Using RNA-sequencing of glaucomatous optic nerve heads, single-cell PCR, and an in-vivo assay, we demonstrate that an up-regulation of astrocytic phagocytosis is an early event after the onset of increased intraocular pressure. We also show that astrocytes in the glial lamina of the optic nerve are apparently functionally heterogeneous. At any time, even in naïve nerves, some of the cells show signs of reactivity—process hypertrophy, high phagocytic activity, and expression of genetic markers of reactivity whereas neighboring cells apparently are inactive. A period of increased intraocular pressure moves more astrocytes towards the reactive phenotype; however, some cells remain unreactive even in glaucomatous nerves. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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33 pages, 10614 KiB  
Article
Heroin Self-Administration and Extinction Increase Prelimbic Cortical Astrocyte–Synapse Proximity and Alter Dendritic Spine Morphometrics That Are Reversed by N-Acetylcysteine
by Benjamin M. Siemsen, Adam R. Denton, Jeffrey Parrila-Carrero, Kaylee N. Hooker, Eilish A. Carpenter, Meagan E. Prescot, Ashley G. Brock, Annaka M. Westphal, Mary-Nan Leath, John A. McFaddin, Thomas C. Jhou, Jacqueline F. McGinty and Michael D. Scofield
Cells 2023, 12(14), 1812; https://doi.org/10.3390/cells12141812 - 08 Jul 2023
Cited by 3 | Viewed by 1381
Abstract
Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin [...] Read more.
Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astrocyte glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observe functional adaptations in the PrL cortical astrocyte following heroin self-administration (SA) and extinction as measured by the electrophysiologically evoked plasmalemmal glutamate transporter 1 (GLT-1)-dependent current. We likewise observed the increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astrocytic plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astrocytic complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased the apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague–Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased the co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, the accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Finally, we show that the NAC treatment and elimination of thrombospondin 2 (TSP-2) block cue-induced heroin relapse. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at the synapses. Additionally, these data demonstrate that NAC reverses PrL cortical heroin SA-and-extinction-induced adaptations in both astrocytes and corticostriatal neurons. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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22 pages, 3587 KiB  
Article
Astrocytic CD44 Deficiency Reduces the Severity of Kainate-Induced Epilepsy
by Patrycja K. Kruk, Karolina Nader, Anna Skupien-Jaroszek, Tomasz Wójtowicz, Anna Buszka, Gabriela Olech-Kochańczyk, Grzegorz M. Wilczynski, Remigiusz Worch, Katarzyna Kalita, Jakub Włodarczyk and Joanna Dzwonek
Cells 2023, 12(11), 1483; https://doi.org/10.3390/cells12111483 - 26 May 2023
Cited by 2 | Viewed by 1568
Abstract
Background: Epilepsy affects millions of people worldwide, yet we still lack a successful treatment for all epileptic patients. Most of the available drugs modulate neuronal activity. Astrocytes, the most abundant cells in the brain, may constitute alternative drug targets. A robust expansion of [...] Read more.
Background: Epilepsy affects millions of people worldwide, yet we still lack a successful treatment for all epileptic patients. Most of the available drugs modulate neuronal activity. Astrocytes, the most abundant cells in the brain, may constitute alternative drug targets. A robust expansion of astrocytic cell bodies and processes occurs after seizures. Highly expressed in astrocytes, CD44 adhesion protein is upregulated during injury and is suggested to be one of the most important proteins associated with epilepsy. It connects the astrocytic cytoskeleton to hyaluronan in the extracellular matrix, influencing both structural and functional aspects of brain plasticity. Methods: Herein, we used transgenic mice with an astrocyte CD44 knockout to evaluate the impact of the hippocampal CD44 absence on the development of epileptogenesis and ultrastructural changes at the tripartite synapse. Results: We demonstrated that local, virally-induced CD44 deficiency in hippocampal astrocytes reduces reactive astrogliosis and decreases the progression of kainic acid-induced epileptogenesis. We also observed that CD44 deficiency resulted in structural changes evident in a higher dendritic spine number along with a lower percentage of astrocyte-synapse contacts, and decreased post-synaptic density size in the hippocampal molecular layer of the dentate gyrus. Conclusions: Overall, our study indicates that CD44 signaling may be important for astrocytic coverage of synapses in the hippocampus and that alterations of astrocytes translate to functional changes in the pathology of epilepsy. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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18 pages, 5029 KiB  
Article
Loss of Astrocytic µ Opioid Receptors Exacerbates Aversion Associated with Morphine Withdrawal in Mice: Role of Mitochondrial Respiration
by Kateryna Murlanova, Yan Jouroukhin, Ksenia Novototskaya-Vlasova, Shovgi Huseynov, Olga Pletnikova, Michael J. Morales, Yun Guan, Atsushi Kamiya, Dwight E. Bergles, David M. Dietz and Mikhail V. Pletnikov
Cells 2023, 12(10), 1412; https://doi.org/10.3390/cells12101412 - 17 May 2023
Cited by 2 | Viewed by 1945
Abstract
Astrocytes express mu/µ opioid receptors, but the function of these receptors remains poorly understood. We evaluated the effects of astrocyte-restricted knockout of µ opioid receptors on reward- and aversion-associated behaviors in mice chronically exposed to morphine. Specifically, one of the floxed alleles of [...] Read more.
Astrocytes express mu/µ opioid receptors, but the function of these receptors remains poorly understood. We evaluated the effects of astrocyte-restricted knockout of µ opioid receptors on reward- and aversion-associated behaviors in mice chronically exposed to morphine. Specifically, one of the floxed alleles of the Oprm1 gene encoding µ opioid receptor 1 was selectively deleted from brain astrocytes in Oprm1 inducible conditional knockout (icKO) mice. These mice did not exhibit changes in locomotor activity, anxiety, or novel object recognition, or in their responses to the acute analgesic effects of morphine. Oprm1 icKO mice displayed increased locomotor activity in response to acute morphine administration but unaltered locomotor sensitization. Oprm1 icKO mice showed normal morphine-induced conditioned place preference but exhibited stronger conditioned place aversion associated with naloxone-precipitated morphine withdrawal. Notably, elevated conditioned place aversion lasted up to 6 weeks in Oprm1 icKO mice. Astrocytes isolated from the brains of Oprm1 icKO mice had unchanged levels of glycolysis but had elevated oxidative phosphorylation. The basal augmentation of oxidative phosphorylation in Oprm1 icKO mice was further exacerbated by naloxone-precipitated withdrawal from morphine and, similar to that for conditioned place aversion, was still present 6 weeks later. Our findings suggest that µ opioid receptors in astrocytes are linked to oxidative phosphorylation and they contribute to long-term changes associated with opioid withdrawal. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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19 pages, 4470 KiB  
Article
STAT3 Drives GFAP Accumulation and Astrocyte Pathology in a Mouse Model of Alexander Disease
by Tracy L. Hagemann, Sierra Coyne, Alder Levin, Liqun Wang, Mel B. Feany and Albee Messing
Cells 2023, 12(7), 978; https://doi.org/10.3390/cells12070978 - 23 Mar 2023
Cited by 1 | Viewed by 2073
Abstract
Alexander disease (AxD) is caused by mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament expressed by astrocytes in the central nervous system. AxD-associated mutations cause GFAP aggregation and astrogliosis, and GFAP is elevated with the astrocyte stress response, [...] Read more.
Alexander disease (AxD) is caused by mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament expressed by astrocytes in the central nervous system. AxD-associated mutations cause GFAP aggregation and astrogliosis, and GFAP is elevated with the astrocyte stress response, exacerbating mutant protein toxicity. Studies in mouse models suggest disease severity is tied to Gfap expression levels, and signal transducer and activator of transcription (STAT)-3 regulates Gfap during astrocyte development and in response to injury and is activated in astrocytes in rodent models of AxD. In this report, we show that STAT3 is also activated in the human disease. To determine whether STAT3 contributes to GFAP elevation, we used a combination of genetic approaches to knockout or reduce STAT3 activation in AxD mouse models. Conditional knockout of Stat3 in cells expressing Gfap reduced Gfap transactivation and prevented protein accumulation. Astrocyte-specific Stat3 knockout in adult mice with existing pathology reversed GFAP accumulation and aggregation. Preventing STAT3 activation reduced markers of reactive astrocytes, stress-related transcripts, and microglial activation, regardless of disease stage or genetic knockout approach. These results suggest that pharmacological inhibition of STAT3 could potentially reduce GFAP toxicity and provide a therapeutic benefit in patients with AxD. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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28 pages, 4788 KiB  
Article
Transcriptional and Chromatin Accessibility Profiling of Neural Stem Cells Differentiating into Astrocytes Reveal Dynamic Signatures Affected under Inflammatory Conditions
by Maria Angeliki S. Pavlou, Kartikeya Singh, Srikanth Ravichandran, Rashi Halder, Nathalie Nicot, Cindy Birck, Luc Grandbarbe, Antonio del Sol and Alessandro Michelucci
Cells 2023, 12(6), 948; https://doi.org/10.3390/cells12060948 - 21 Mar 2023
Viewed by 2118
Abstract
Astrocytes arise from multipotent neural stem cells (NSCs) and represent the most abundant cell type of the central nervous system (CNS), playing key roles in the developing and adult brain. Since the differentiation of NSCs towards a gliogenic fate is a precisely timed [...] Read more.
Astrocytes arise from multipotent neural stem cells (NSCs) and represent the most abundant cell type of the central nervous system (CNS), playing key roles in the developing and adult brain. Since the differentiation of NSCs towards a gliogenic fate is a precisely timed and regulated process, its perturbation gives rise to dysfunctional astrocytic phenotypes. Inflammation, which often underlies neurological disorders, including neurodevelopmental disorders and brain tumors, disrupts the accurate developmental process of NSCs. However, the specific consequences of an inflammatory environment on the epigenetic and transcriptional programs underlying NSCs’ differentiation into astrocytes is unexplored. Here, we address this gap by profiling in mice glial precursors from neural tissue derived from early embryonic stages along their astrocytic differentiation trajectory in the presence or absence of tumor necrosis factor (TNF), a master pro-inflammatory cytokine. By using a combination of RNA- and ATAC-sequencing approaches, together with footprint and integrated gene regulatory network analyses, we here identify key differences during the differentiation of NSCs into astrocytes under physiological and inflammatory settings. In agreement with its role to turn cells resistant to inflammatory challenges, we detect Nrf2 as a master transcription factor supporting the astrocytic differentiation under TNF exposure. Further, under these conditions, we unravel additional transcriptional regulatory hubs, including Stat3, Smad3, Cebpb, and Nfkb2, highlighting the interplay among pathways underlying physiological astrocytic developmental processes and those involved in inflammatory responses, resulting in discrete astrocytic phenotypes. Overall, our study reports key transcriptional and epigenetic changes leading to the identification of molecular regulators of astrocytic differentiation. Furthermore, our analyses provide a valuable resource for understanding inflammation-induced astrocytic phenotypes that might contribute to the development and progression of CNS disorders with an inflammatory component. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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19 pages, 9474 KiB  
Article
Cortical Pathology in Vanishing White Matter
by Jodie H. K. Man, Charlotte A. G. H. van Gelder, Marjolein Breur, Daniel Okkes, Douwe Molenaar, Sophie van der Sluis, Truus Abbink, Maarten Altelaar, Marjo S. van der Knaap and Marianna Bugiani
Cells 2022, 11(22), 3581; https://doi.org/10.3390/cells11223581 - 12 Nov 2022
Cited by 2 | Viewed by 2080
Abstract
Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. [...] Read more.
Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. Here, we provide a comprehensive analysis of the VWM cortex. We employed high-resolution-mass-spectrometry-based proteomics and immunohistochemistry to gain insight into possible molecular disease mechanisms in the cortices of VWM patients. The proteome analysis revealed 268 differentially expressed proteins in the VWM cortices compared to the controls. A majority of these proteins formed a major protein interaction network. A subsequent gene ontology analysis identified enrichment for terms such as cellular metabolism, particularly mitochondrial activity. Importantly, some of the proteins with the most prominent changes in expression were found in astrocytes, indicating cortical astrocytic involvement. Indeed, we confirmed that VWM cortical astrocytes exhibit morphological changes and are less complex in structure than control cells. Our findings also suggest that these astrocytes are immature and not reactive. Taken together, we provide insights into cortical involvement in VWM, which has to be taken into account when developing therapeutic strategies. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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16 pages, 4220 KiB  
Article
Spatial and Temporal Diversity of Astrocyte Phenotypes in Spinocerebellar Ataxia Type 1 Mice
by Juao-Guilherme Rosa, Katherine Hamel, Carrie Sheeler, Ella Borgenheimer, Stephen Gilliat, Alyssa Soles, Ferris J. Ghannoum, Kaelin Sbrocco, Hillary P. Handler, Orion Rainwater, Ryan Kang and Marija Cvetanovic
Cells 2022, 11(20), 3323; https://doi.org/10.3390/cells11203323 - 21 Oct 2022
Cited by 3 | Viewed by 1806
Abstract
While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene Ataxin1 ( [...] Read more.
While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene Ataxin1 (ATXN1). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex, of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1. We found brain region-specific changes in astrocyte density and GFAP expression and area, early in the disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain region-specific manner and correlated with neuronal activity, indicating that astrocytes may compensate or exacerbate neuronal dysfunction. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions, indicating loss of astrocyte functions. We observed no obvious correlation between spatiotemporal changes in microglia and spatiotemporal astrocyte alterations, indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain region and disease stage-specific manner. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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22 pages, 2268 KiB  
Article
Gene Enrichment Analysis of Astrocyte Subtypes in Psychiatric Disorders and Psychotropic Medication Datasets
by Xiaolu Zhang, Alyssa Wolfinger, Xiaojun Wu, Rawan Alnafisah, Ali Imami, Abdul-rizaq Hamoud, Anna Lundh, Vladimir Parpura, Robert E. McCullumsmith, Rammohan Shukla and Sinead M. O’Donovan
Cells 2022, 11(20), 3315; https://doi.org/10.3390/cells11203315 - 21 Oct 2022
Cited by 3 | Viewed by 1694
Abstract
Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications [...] Read more.
Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications (antipsychotics, antidepressants and mood stabilizers). We also carried out qPCR analyses and “look-up” studies to assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified gene enrichment of different astrocyte subtypes in psychiatric disorders. The highest level of enrichment was found in schizophrenia, supporting a role for astrocytes in this disorder. We also found differential enrichment of astrocyte subtypes associated with specific biological processes, highlighting the complex responses of astrocytes under pathological conditions. Enrichment of protein phosphorylation in astrocytes and disease was confirmed by biochemical analysis. Analysis of LINCS chemical perturbagen gene signatures also found that kinase inhibitors were highly discordant with astrocyte-SCZ associated gene signatures. However, we found that common gene enrichment of different psychotropic medications and astrocyte subtypes was limited. These results were confirmed by “look-up” studies and qPCR analysis, which also reported little effect of psychotropic medications on common astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Conversely, antipsychotic medication does affect astrocyte gene marker expression in postmortem schizophrenia brain tissue, supporting specific astrocyte responses in different pathological conditions. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in psychiatric disorders and offers insights into targeting astrocytes therapeutically. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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25 pages, 4586 KiB  
Article
The CaMKII/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes
by Maria Stefania Brignone, Angela Lanciotti, Antonio Michelucci, Cinzia Mallozzi, Serena Camerini, Luigi Catacuzzeno, Luigi Sforna, Martino Caramia, Maria Cristina D’Adamo, Marina Ceccarini, Paola Molinari, Pompeo Macioce, Gianfranco Macchia, Tamara Corinna Petrucci, Mauro Pessia, Sergio Visentin and Elena Ambrosini
Cells 2022, 11(17), 2656; https://doi.org/10.3390/cells11172656 - 26 Aug 2022
Cited by 6 | Viewed by 3049
Abstract
Astrocytes, the main glial cells of the central nervous system, play a key role in brain volume control due to their intimate contacts with cerebral blood vessels and the expression of a distinctive equipment of proteins involved in solute/water transport. Among these is [...] Read more.
Astrocytes, the main glial cells of the central nervous system, play a key role in brain volume control due to their intimate contacts with cerebral blood vessels and the expression of a distinctive equipment of proteins involved in solute/water transport. Among these is MLC1, a protein highly expressed in perivascular astrocytes and whose mutations cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), an incurable leukodystrophy characterized by macrocephaly, chronic brain edema, cysts, myelin vacuolation, and astrocyte swelling. Although, in astrocytes, MLC1 mutations are known to affect the swelling-activated chloride currents (ICl,swell) mediated by the volume-regulated anion channel (VRAC), and the regulatory volume decrease, MLC1′s proper function is still unknown. By combining molecular, biochemical, proteomic, electrophysiological, and imaging techniques, we here show that MLC1 is a Ca2+/Calmodulin-dependent protein kinase II (CaMKII) target protein, whose phosphorylation, occurring in response to intracellular Ca2+ release, potentiates VRAC-mediated ICl,swell. Overall, these findings reveal that MLC1 is a Ca2+-regulated protein, linking volume regulation to Ca2+ signaling in astrocytes. This knowledge provides new insight into the MLC1 protein function and into the mechanisms controlling ion/water exchanges in the brain, which may help identify possible molecular targets for the treatment of MLC and other pathological conditions caused by astrocyte swelling and brain edema. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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Review

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19 pages, 1623 KiB  
Review
Astrocytes Are a Key Target for Neurotropic Viral Infection
by Maja Potokar, Robert Zorec and Jernej Jorgačevski
Cells 2023, 12(18), 2307; https://doi.org/10.3390/cells12182307 - 19 Sep 2023
Cited by 1 | Viewed by 1167
Abstract
Astrocytes are increasingly recognized as important viral host cells in the central nervous system. These cells can produce relatively high quantities of new virions. In part, this can be attributed to the characteristics of astrocyte metabolism and its abundant and dynamic cytoskeleton network. [...] Read more.
Astrocytes are increasingly recognized as important viral host cells in the central nervous system. These cells can produce relatively high quantities of new virions. In part, this can be attributed to the characteristics of astrocyte metabolism and its abundant and dynamic cytoskeleton network. Astrocytes are anatomically localized adjacent to interfaces between blood capillaries and brain parenchyma and between blood capillaries and brain ventricles. Moreover, astrocytes exhibit a larger membrane interface with the extracellular space than neurons. These properties, together with the expression of various and numerous viral entry receptors, a relatively high rate of endocytosis, and morphological plasticity of intracellular organelles, render astrocytes important target cells in neurotropic infections. In this review, we describe factors that mediate the high susceptibility of astrocytes to viral infection and replication, including the anatomic localization of astrocytes, morphology, expression of viral entry receptors, and various forms of autophagy. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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16 pages, 5216 KiB  
Review
The Role of Aquaporins in Spinal Cord Injury
by Terese A. Garcia, Carrie R. Jonak and Devin K. Binder
Cells 2023, 12(13), 1701; https://doi.org/10.3390/cells12131701 - 23 Jun 2023
Cited by 1 | Viewed by 1123
Abstract
Edema formation following traumatic spinal cord injury (SCI) exacerbates secondary injury, and the severity of edema correlates with worse neurological outcome in human patients. To date, there are no effective treatments to directly resolve edema within the spinal cord. The aquaporin-4 (AQP4) water [...] Read more.
Edema formation following traumatic spinal cord injury (SCI) exacerbates secondary injury, and the severity of edema correlates with worse neurological outcome in human patients. To date, there are no effective treatments to directly resolve edema within the spinal cord. The aquaporin-4 (AQP4) water channel is found on plasma membranes of astrocytic endfeet in direct contact with blood vessels, the glia limitans in contact with the cerebrospinal fluid, and ependyma around the central canal. Local expression at these tissue–fluid interfaces allows AQP4 channels to play an important role in the bidirectional regulation of water homeostasis under normal conditions and following trauma. In this review, we consider the available evidence regarding the potential role of AQP4 in edema after SCI. Although more work remains to be carried out, the overall evidence indicates a critical role for AQP4 channels in edema formation and resolution following SCI and the therapeutic potential of AQP4 modulation in edema resolution and functional recovery. Further work to elucidate the expression and subcellular localization of AQP4 during specific phases after SCI will inform the therapeutic modulation of AQP4 for the optimization of histological and neurological outcomes. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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12 pages, 3474 KiB  
Review
Role of Impaired Astrocyte Gap Junction Coupling in Epileptogenesis
by Peter Bedner and Christian Steinhäuser
Cells 2023, 12(12), 1669; https://doi.org/10.3390/cells12121669 - 20 Jun 2023
Cited by 6 | Viewed by 1446
Abstract
The gap-junction-coupled astroglial network plays a central role in the regulation of neuronal activity and synchronisation, but its involvement in the pathogenesis of neuronal diseases is not yet understood. Here, we present the current state of knowledge about the impact of impaired glial [...] Read more.
The gap-junction-coupled astroglial network plays a central role in the regulation of neuronal activity and synchronisation, but its involvement in the pathogenesis of neuronal diseases is not yet understood. Here, we present the current state of knowledge about the impact of impaired glial coupling in the development and progression of epilepsy and discuss whether astrocytes represent alternative therapeutic targets. We focus mainly on temporal lobe epilepsy (TLE), which is the most common form of epilepsy in adults and is characterised by high therapy resistance. Functional data from TLE patients and corresponding experimental models point to a complete loss of astrocytic coupling, but preservation of the gap junction forming proteins connexin43 and connexin30 in hippocampal sclerosis. Several studies further indicate that astrocyte uncoupling is a causal event in the initiation of TLE, as it occurs very early in epileptogenesis, clearly preceding dysfunctional changes in neurons. However, more research is needed to fully understand the role of gap junction channels in epilepsy and to develop safe and effective therapeutic strategies targeting astrocytes. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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12 pages, 922 KiB  
Review
Astrocyte Signature in Alzheimer’s Disease Continuum through a Multi-PET Tracer Imaging Perspective
by Igor C. Fontana, Miriam Scarpa, Mona-Lisa Malarte, Filipa M. Rocha, Sira Ausellé-Bosch, Marina Bluma, Marco Bucci, Konstantinos Chiotis, Amit Kumar and Agneta Nordberg
Cells 2023, 12(11), 1469; https://doi.org/10.3390/cells12111469 - 24 May 2023
Viewed by 2110
Abstract
Reactive astrogliosis is an early event in the continuum of Alzheimer’s disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings [...] Read more.
Reactive astrogliosis is an early event in the continuum of Alzheimer’s disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aβ plaques, tau pathology, and neurodegeneration in AD. Furthermore, considering the current view of reactive astrogliosis heterogeneity—more than one subtype of astrocyte involved—in AD, we discuss how astrocytic body fluid biomarkers might fit into trajectories different from that of astrocytic PET imaging. Future research focusing on the development of innovative astrocytic PET radiotracers and fluid biomarkers may provide further insights into the heterogeneity of reactive astrogliosis and improve the detection of AD in its early stages. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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27 pages, 1453 KiB  
Review
Astrocytes: Dissecting Their Diverse Roles in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
by Chiara F. Valori, Claudia Sulmona, Liliana Brambilla and Daniela Rossi
Cells 2023, 12(11), 1450; https://doi.org/10.3390/cells12111450 - 23 May 2023
Cited by 7 | Viewed by 2493
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders often co-occurring in the same patient, a feature that suggests a common origin of the two diseases. Consistently, pathological inclusions of the same proteins as well as mutations in the same [...] Read more.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders often co-occurring in the same patient, a feature that suggests a common origin of the two diseases. Consistently, pathological inclusions of the same proteins as well as mutations in the same genes can be identified in both ALS/FTD. Although many studies have described several disrupted pathways within neurons, glial cells are also regarded as crucial pathogenetic contributors in ALS/FTD. Here, we focus our attention on astrocytes, a heterogenous population of glial cells that perform several functions for optimal central nervous system homeostasis. Firstly, we discuss how post-mortem material from ALS/FTD patients supports astrocyte dysfunction around three pillars: neuroinflammation, abnormal protein aggregation, and atrophy/degeneration. Furthermore, we summarize current attempts at monitoring astrocyte functions in living patients using either novel imaging strategies or soluble biomarkers. We then address how astrocyte pathology is recapitulated in animal and cellular models of ALS/FTD and how we used these models both to understand the molecular mechanisms driving glial dysfunction and as platforms for pre-clinical testing of therapeutics. Finally, we present the current clinical trials for ALS/FTD, restricting our discussion to treatments that modulate astrocyte functions, directly or indirectly. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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19 pages, 1519 KiB  
Review
The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review
by Ali Sepehrinezhad, Fin Stolze Larsen, Rezan Ashayeri Ahmadabad, Ali Shahbazi and Sajad Sahab Negah
Cells 2023, 12(7), 979; https://doi.org/10.3390/cells12070979 - 23 Mar 2023
Cited by 3 | Viewed by 2202
Abstract
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized [...] Read more.
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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12 pages, 2573 KiB  
Review
Role of Astrocytes in the Pathophysiology of Lafora Disease and Other Glycogen Storage Disorders
by Jordi Duran
Cells 2023, 12(5), 722; https://doi.org/10.3390/cells12050722 - 24 Feb 2023
Cited by 1 | Viewed by 2520
Abstract
Lafora disease is a rare disorder caused by loss of function mutations in either the EPM2A or NHLRC1 gene. The initial symptoms of this condition are most commonly epileptic seizures, but the disease progresses rapidly with dementia, neuropsychiatric symptoms, and cognitive deterioration and [...] Read more.
Lafora disease is a rare disorder caused by loss of function mutations in either the EPM2A or NHLRC1 gene. The initial symptoms of this condition are most commonly epileptic seizures, but the disease progresses rapidly with dementia, neuropsychiatric symptoms, and cognitive deterioration and has a fatal outcome within 5–10 years after onset. The hallmark of the disease is the accumulation of poorly branched glycogen in the form of aggregates known as Lafora bodies in the brain and other tissues. Several reports have demonstrated that the accumulation of this abnormal glycogen underlies all the pathologic traits of the disease. For decades, Lafora bodies were thought to accumulate exclusively in neurons. However, it was recently identified that most of these glycogen aggregates are present in astrocytes. Importantly, astrocytic Lafora bodies have been shown to contribute to pathology in Lafora disease. These results identify a primary role of astrocytes in the pathophysiology of Lafora disease and have important implications for other conditions in which glycogen abnormally accumulates in astrocytes, such as Adult Polyglucosan Body disease and the buildup of Corpora amylacea in aged brains. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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15 pages, 1744 KiB  
Review
Roles of Astrocytic Endothelin ETB Receptor in Traumatic Brain Injury
by Shotaro Michinaga, Shigeru Hishinuma and Yutaka Koyama
Cells 2023, 12(5), 719; https://doi.org/10.3390/cells12050719 - 24 Feb 2023
Cited by 2 | Viewed by 1704
Abstract
Traumatic brain injury (TBI) is an intracranial injury caused by accidents, falls, or sports. The production of endothelins (ETs) is increased in the injured brain. ET receptors are classified into distinct types, including ETA receptor (ETA-R) and ETB receptor [...] Read more.
Traumatic brain injury (TBI) is an intracranial injury caused by accidents, falls, or sports. The production of endothelins (ETs) is increased in the injured brain. ET receptors are classified into distinct types, including ETA receptor (ETA-R) and ETB receptor (ETB-R). ETB-R is highly expressed in reactive astrocytes and upregulated by TBI. Activation of astrocytic ETB-R promotes conversion to reactive astrocytes and the production of astrocyte-derived bioactive factors, including vascular permeability regulators and cytokines, which cause blood–brain barrier (BBB) disruption, brain edema, and neuroinflammation in the acute phase of TBI. ETB-R antagonists alleviate BBB disruption and brain edema in animal models of TBI. The activation of astrocytic ETB receptors also enhances the production of various neurotrophic factors. These astrocyte-derived neurotrophic factors promote the repair of the damaged nervous system in the recovery phase of patients with TBI. Thus, astrocytic ETB-R is expected to be a promising drug target for TBI in both the acute and recovery phases. This article reviews recent observations on the role of astrocytic ETB receptors in TBI. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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19 pages, 1358 KiB  
Review
Role of Astrocytes in Parkinson’s Disease Associated with Genetic Mutations and Neurotoxicants
by Sanghoon Kim, Edward Pajarillo, Ivan Nyarko-Danquah, Michael Aschner and Eunsook Lee
Cells 2023, 12(4), 622; https://doi.org/10.3390/cells12040622 - 15 Feb 2023
Cited by 8 | Viewed by 4461
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the aggregation of Lewy bodies in the basal ganglia, resulting in movement impairment referred to as parkinsonism. However, the etiology of PD is not well known, with genetic [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the aggregation of Lewy bodies in the basal ganglia, resulting in movement impairment referred to as parkinsonism. However, the etiology of PD is not well known, with genetic factors accounting only for 10–15% of all PD cases. The pathogenetic mechanism of PD is not completely understood, although several mechanisms, such as oxidative stress and inflammation, have been suggested. Understanding the mechanisms of PD pathogenesis is critical for developing highly efficacious therapeutics. In the PD brain, dopaminergic neurons degenerate mainly in the basal ganglia, but recently emerging evidence has shown that astrocytes also significantly contribute to dopaminergic neuronal death. In this review, we discuss the role of astrocytes in PD pathogenesis due to mutations in α-synuclein (PARK1), DJ-1 (PARK7), parkin (PARK2), leucine-rich repeat kinase 2 (LRRK2, PARK8), and PTEN-induced kinase 1 (PINK1, PARK6). We also discuss PD experimental models using neurotoxins, such as paraquat, rotenone, 6-hydroxydopamine, and MPTP/MPP+. A more precise and comprehensive understanding of astrocytes’ modulatory roles in dopaminergic neurodegeneration in PD will help develop novel strategies for effective PD therapeutics. Full article
(This article belongs to the Special Issue Astrocytes in CNS Disorders)
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