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TSPO and Brain Disorders
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TSPO and Brain Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 36950

Special Issue Editors

Dr. Leo Veenman

E-Mail Website
Guest Editor
The Ruth and Bruce Rappaport Faculty of Medicine, Department of Neuroscience, Haifa, Israel
Interests: TSPO; brain trauma; brain disease; neurodegeneration; mental disorder; astrocytes microglia, neurons; inflammation; treatment
Special Issues, Collections and Topics in MDPI journals
Prof. Moshe Gavish

E-Mail Website
Guest Editor
Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Sara & Moshe Zisapel Nanoelectronics Center, Technion City, Haifa 32000, Israel
Interests: drug development for treatment of brain diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Abraham Weizman

E-Mail Website
Co-Guest Editor
Research Unit, Geha Mental Health Center and the Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Interests: TSPO; psychiatric disorders; psychopharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The TSPO (translocator protein) was discovered in the early 1970s. It is becoming more and more understood that the TSPO can be targeted to treat neurological disorders (diseases as well as injuries). TSPO appears to modulate the generation of various molecules, as well as the transport of such  molecules over the outer mitochondrial membrane, for example, Ca++, ATP, ROS, cholesterol, tetrapyrroles, and cytochrome c. These molecules play a part in the regulation of programmed cell death, gene expression, and metabolism. Furthermore, the TSPO regulates inflammation and immune responses, as well as cell proliferation, migration, differentiation, and adhesion. These are all essential functions related to the various brain disorders and their healing. To address associated questions regarding these functions, including their roles in neurological disorders, numerous synthetic TSPO ligands have been designed, generally based on the tricyclic structure of benzodiazepines. Actually, that was how TSPO was discovered, serendipitously, as the benzodiazepine diazepam was found to bind to an unknown protein present outside the brain. Hence, TSPO’s early name was the peripheral benzodiazepine receptor. Now, we are starting to understand that synthetic and natural ligands bind to various sites on the TSPO. Hopefully, the expansion of our knowledge on TSPO will lead to novel treatments for various brain disorders. Submissions dealing with all of these topics are welcome.

Dr. Leo Veenman
Prof. Moshe Gavish
Prof. Dr. Abraham Weizman
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • TSPO
  • brain trauma
  • brain disease
  • neurodegeneration
  • mental disorder
  • astrocytes
  • microglia
  • neurons
  • inflammation
  • treatment

Published Papers (6 papers)

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Research

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21 pages, 3775 KiB  
Article
Microglial Pro-Inflammatory and Anti-Inflammatory Phenotypes Are Modulated by Translocator Protein Activation
by Eleonora Da Pozzo, Chiara Tremolanti, Barbara Costa, Chiara Giacomelli, Vladimir M. Milenkovic, Stefanie Bader, Christian H. Wetzel, Rainer Rupprecht, Sabrina Taliani, Federico Da Settimo and Claudia Martini
Int. J. Mol. Sci. 2019, 20(18), 4467; https://doi.org/10.3390/ijms20184467 - 10 Sep 2019
Cited by 58 | Viewed by 5342
Abstract
A key role of the mitochondrial Translocator Protein 18 KDa (TSPO) in neuroinflammation has been recently proposed. However, little is known about TSPO-activated pathways underlying the modulation of reactive microglia. In the present work, the TSPO activation was explored in an in vitro [...] Read more.
A key role of the mitochondrial Translocator Protein 18 KDa (TSPO) in neuroinflammation has been recently proposed. However, little is known about TSPO-activated pathways underlying the modulation of reactive microglia. In the present work, the TSPO activation was explored in an in vitro human primary microglia model (immortalized C20 cells) under inflammatory stimulus. Two different approaches were used with the aim to (i) pharmacologically amplify or (ii) silence, by the lentiviral short hairpin RNA, the TSPO physiological function. In the TSPO pharmacological stimulation model, the synthetic steroidogenic selective ligand XBD-173 attenuated the activation of microglia. Indeed, it reduces and increases the release of pro-inflammatory and anti-inflammatory cytokines, respectively. Such ligand-induced effects were abolished when C20 cells were treated with the steroidogenesis inhibitor aminoglutethimide. This suggests a role for neurosteroids in modulating the interleukin production. The highly steroidogenic ligand XBD-173 attenuated the neuroinflammatory response more effectively than the poorly steroidogenic ones, which suggests that the observed modulation on the cytokine release may be influenced by the levels of produced neurosteroids. In the TSPO silencing model, the reduction of TSPO caused a more inflamed phenotype with respect to scrambled cells. Similarly, during the inflammatory response, the TSPO silencing increased and reduced the release of pro-inflammatory and anti-inflammatory cytokines, respectively. In conclusion, the obtained results are in favor of a homeostatic role for TSPO in the context of dynamic balance between anti-inflammatory and pro-inflammatory mediators in the human microglia-mediated inflammatory response. Interestingly, our preliminary results propose that the TSPO expression could be stimulated by NF-κB during activation of the inflammatory response. Full article
(This article belongs to the Special Issue TSPO and Brain Disorders)
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15 pages, 2506 KiB  
Article
CRISPR-Cas9 Mediated TSPO Gene Knockout alters Respiration and Cellular Metabolism in Human Primary Microglia Cells
by Vladimir M. Milenkovic, Dounia Slim, Stefanie Bader, Victoria Koch, Elena-Sofia Heinl, David Alvarez-Carbonell, Caroline Nothdurfter, Rainer Rupprecht and Christian H. Wetzel
Int. J. Mol. Sci. 2019, 20(13), 3359; https://doi.org/10.3390/ijms20133359 - 9 Jul 2019
Cited by 38 | Viewed by 6681
Abstract
The 18 kDa translocator protein (TSPO) is an evolutionary conserved cholesterol binding protein localized in the outer mitochondrial membrane. It has been implicated in the regulation of various cellular processes including oxidative stress, proliferation, apoptosis, and steroid hormone biosynthesis. Since the expression of [...] Read more.
The 18 kDa translocator protein (TSPO) is an evolutionary conserved cholesterol binding protein localized in the outer mitochondrial membrane. It has been implicated in the regulation of various cellular processes including oxidative stress, proliferation, apoptosis, and steroid hormone biosynthesis. Since the expression of TSPO in activated microglia is upregulated in various neuroinflammatory and neurodegenerative disorders, we set out to examine the role of TSPO in an immortalized human microglia C20 cell line. To this end, we performed a dual approach and used (i) lentiviral shRNA silencing to reduce TSPO expression, and (ii) the CRISPR/Cas9 technology to generate complete TSPO knockout microglia cell lines. Functional characterization of control and TSPO knockdown as well as knockout cells, revealed only low de novo steroidogenesis in C20 cells, which was not dependent on the level of TSPO expression or influenced by the treatment with TSPO-specific ligands. In contrast to TSPO knockdown C20 cells, which did not show altered mitochondrial function, the TSPO deficient knockout cells displayed a significantly decreased mitochondrial membrane potential and cytosolic Ca2+ levels, as well as reduced respiratory function. Performing the rescue experiment by lentiviral overexpression of TSPO in knockout cells, increased oxygen consumption and restored respiratory function. Our study provides further evidence for a significant role of TSPO in cellular and mitochondrial metabolism and demonstrates that different phenotypes of mitochondrial function are dependent on the level of TSPO expression. Full article
(This article belongs to the Special Issue TSPO and Brain Disorders)
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14 pages, 2334 KiB  
Article
Reduction of Traumatic Brain Damage by Tspo Ligand Etifoxine
by Mona Shehadeh, Eilam Palzur, Liat Apel and Jean Francois Soustiel
Int. J. Mol. Sci. 2019, 20(11), 2639; https://doi.org/10.3390/ijms20112639 - 29 May 2019
Cited by 19 | Viewed by 3234
Abstract
Experimental studies have shown that ligands of the 18 kDa translocator protein can reduce neuronal damage induced by traumatic brain injury by protecting mitochondria and preventing metabolic crisis. Etifoxine, an anxiolytic drug and 18 kDa translocator protein ligand, has shown beneficial effects in [...] Read more.
Experimental studies have shown that ligands of the 18 kDa translocator protein can reduce neuronal damage induced by traumatic brain injury by protecting mitochondria and preventing metabolic crisis. Etifoxine, an anxiolytic drug and 18 kDa translocator protein ligand, has shown beneficial effects in the models of peripheral nerve neuropathy. The present study investigates the potential effect of etifoxine as a neuroprotective agent in traumatic brain injury (TBI). For this purpose, the effect of etifoxine on lesion volume and modified neurological severity score at 4 weeks was tested in Sprague–Dawley adult male rats submitted to cortical impact contusion. Effects of etifoxine treatment on neuronal survival and apoptosis were also assessed by immune stains in the perilesional area. Etifoxine induced a significant reduction in the lesion volume compared to nontreated animals in a dose-dependent fashion with a similar effect on neurological outcome at four weeks that correlated with enhanced neuron survival and reduced apoptotic activity. These results are consistent with the neuroprotective effect of etifoxine in TBI that may justify further translational research. Full article
(This article belongs to the Special Issue TSPO and Brain Disorders)
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21 pages, 17720 KiB  
Article
Antioxidant Properties of Fucoidan Alleviate Acceleration and Exacerbation of Hippocampal Neuronal Death Following Transient Global Cerebral Ischemia in High-Fat Diet-Induced Obese Gerbils
by Ji Hyeon Ahn, Myoung Cheol Shin, Dae Won Kim, Hyunjung Kim, Minah Song, Tae-Kyeong Lee, Jae-Chul Lee, Hyeyoung Kim, Jun Hwi Cho, Young-Myeong Kim, Jong-Dai Kim, Soo Young Choi, Moo-Ho Won and Joon Ha Park
Int. J. Mol. Sci. 2019, 20(3), 554; https://doi.org/10.3390/ijms20030554 - 28 Jan 2019
Cited by 31 | Viewed by 4416
Abstract
Fucoidan, a natural sulfated polysaccharide, displays various biological activities including antioxidant properties. We examined the neuroprotective effect of fucoidan against transient global cerebral ischemia (tGCI) in high-fat diet (HFD)-induced obese gerbils and its related mechanisms. Gerbils received HFD for 12 weeks and fucoidan [...] Read more.
Fucoidan, a natural sulfated polysaccharide, displays various biological activities including antioxidant properties. We examined the neuroprotective effect of fucoidan against transient global cerebral ischemia (tGCI) in high-fat diet (HFD)-induced obese gerbils and its related mechanisms. Gerbils received HFD for 12 weeks and fucoidan (50 mg/kg) daily for the last 5 days during HFD exposure, and they were subjected to 5-min tGCI. Pyramidal cell death was observed only in the CA 1 area (CA1) of the hippocampus in non-obese gerbils 5 days after tGCI. However, in obese gerbils, pyramidal cell death in the CA1 and CA2/3 occurred at 2 days and 5 days, respectively, after tGCI. In the obese gerbils, oxidative stress indicators (dihydroethidium, 8-hydroxyguanine and 4-hydroxy-2-nonenal) were significantly enhanced and antioxidant enzymes (SOD1 and SOD2) were significantly reduced in pre- and post-ischemic phases compared to the non-obese gerbils. Fucoidan treatment attenuated acceleration and exacerbation of tGCI-induced neuronal death in the CA1–3, showing that oxidative stress was significantly reduced, and antioxidant enzymes were significantly increased in pre- and post-ischemic phases. These findings indicate that pretreated fucoidan can relieve the acceleration and exacerbation of ischemic brain injury in an obese state via the attenuation of obesity-induced severe oxidative damage. Full article
(This article belongs to the Special Issue TSPO and Brain Disorders)
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Review

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17 pages, 7191 KiB  
Review
VDAC1 and the TSPO: Expression, Interactions, and Associated Functions in Health and Disease States
by Varda Shoshan-Barmatz, Srinivas Pittala and Dario Mizrachi
Int. J. Mol. Sci. 2019, 20(13), 3348; https://doi.org/10.3390/ijms20133348 - 8 Jul 2019
Cited by 65 | Viewed by 7889
Abstract
The translocator protein (TSPO), located at the outer mitochondrial membrane (OMM), serves multiple functions and contributes to numerous processes, including cholesterol import, mitochondrial metabolism, apoptosis, cell proliferation, Ca2+ signaling, oxidative stress, and inflammation. TSPO forms a complex with the voltage-dependent anion channel [...] Read more.
The translocator protein (TSPO), located at the outer mitochondrial membrane (OMM), serves multiple functions and contributes to numerous processes, including cholesterol import, mitochondrial metabolism, apoptosis, cell proliferation, Ca2+ signaling, oxidative stress, and inflammation. TSPO forms a complex with the voltage-dependent anion channel (VDAC), a protein that mediates the flux of ions, including Ca2+, nucleotides, and metabolites across the OMM, controls metabolism and apoptosis and interacts with many proteins. This review focuses on the two OMM proteins TSPO and VDAC1, addressing their structural interaction and associated functions. TSPO appears to be involved in the generation of reactive oxygen species, proposed to represent the link between TSPO activation and VDAC, thus playing a role in apoptotic cell death. In addition, expression of the two proteins in healthy brains and diseased states is considered, as is the relationship between TSPO and VDAC1 expression. Both proteins are over-expressed in in brains from Alzheimer’s disease patients. Finally, TSPO expression levels were proposed as a biomarker of some neuropathological settings, while TSPO-interacting ligands have been considered as a potential basis for drug development. Full article
(This article belongs to the Special Issue TSPO and Brain Disorders)
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21 pages, 1316 KiB  
Review
Recent Developments in TSPO PET Imaging as A Biomarker of Neuroinflammation in Neurodegenerative Disorders
by Eryn L. Werry, Fiona M. Bright, Olivier Piguet, Lars M. Ittner, Glenda M. Halliday, John R. Hodges, Matthew C. Kiernan, Clement T. Loy, Jillian J. Kril and Michael Kassiou
Int. J. Mol. Sci. 2019, 20(13), 3161; https://doi.org/10.3390/ijms20133161 - 28 Jun 2019
Cited by 166 | Viewed by 8655
Abstract
Neuroinflammation is an inflammatory response in the brain and spinal cord, which can involve the activation of microglia and astrocytes. It is a common feature of many central nervous system disorders, including a range of neurodegenerative disorders. An overlap between activated microglia, pro-inflammatory [...] Read more.
Neuroinflammation is an inflammatory response in the brain and spinal cord, which can involve the activation of microglia and astrocytes. It is a common feature of many central nervous system disorders, including a range of neurodegenerative disorders. An overlap between activated microglia, pro-inflammatory cytokines and translocator protein (TSPO) ligand binding was shown in early animal studies of neurodegeneration. These findings have been translated in clinical studies, where increases in TSPO positron emission tomography (PET) signal occur in disease-relevant areas across a broad spectrum of neurodegenerative diseases. While this supports the use of TSPO PET as a biomarker to monitor response in clinical trials of novel neurodegenerative therapeutics, the clinical utility of current TSPO PET radioligands has been hampered by the lack of high affinity binding to a prevalent form of polymorphic TSPO (A147T) compared to wild type TSPO. This review details recent developments in exploration of ligand-sensitivity to A147T TSPO that have yielded ligands with improved clinical utility. In addition to developing a non-discriminating TSPO ligand, the final frontier of TSPO biomarker research requires developing an understanding of the cellular and functional interpretation of the TSPO PET signal. Recent insights resulting from single cell analysis of microglial phenotypes are reviewed. Full article
(This article belongs to the Special Issue TSPO and Brain Disorders)
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