Global Deletion of TSPO Does Not Affect the Viability and Gene Expression Profile

Wang, Huaishan; Zhai, Kangle; Xue, Yingchao; Yang, Jia; Yang, Qi; Fu, Yi; Hu, Yu; Liu, Fang; Wang, Weiqing; Cui, Lianxian; Chen, Hui; Zhang, Jianmin; He, Wei

doi:10.1371/journal.pone.0167307

Cited by 34 publications

(37 citation statements)

References 49 publications

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“…Constitutive expression of TSPO is high in most peripheral organs, including the adrenals, kidney, spleen, and liver, but low and often below detection limits in the normal healthy brain [ 3 , 47 , 48 , 49 ]. However, following injury or during actively progressing tissue pathology, high levels of TSPO can be found in the brain.…”

Section: Discussionmentioning

confidence: 99%

Cellular Sources and Regional Variations in the Expression of the Neuroinflammatory Marker Translocator Protein (TSPO) in the Normal Brain

Betlazar

Harrison-Brown

Middleton

et al. 2018

IJMS

111

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The inducible expression of the mitochondrial translocator protein 18 kDa (TSPO) by activated microglia is a prominent, regular feature of acute and chronic-progressive brain pathology. This expression is also the rationale for the continual development of new TSPO binding molecules for the diagnosis of “neuroinflammation” by molecular imaging. However, there is in the normal brain an ill-defined, low-level constitutive expression of TSPO. Taking advantage of healthy TSPO knockout mouse brain tissue to validate TSPO antibody specificity, this study uses immunohistochemistry to determine the regional distribution and cellular sources of TSPO in the normal mouse brain. Fluorescence microscopy revealed punctate TSPO immunostaining in vascular endothelial cells throughout the brain. In the olfactory nerve layers and glomeruli of the olfactory bulb, choroid plexus and ependymal layers, we confirm constitutive TSPO expression levels similar to peripheral organs, while some low TSPO expression is present in regions of known neurogenesis, as well as cerebellar Purkinje cells. The distributed-sparse expression of TSPO in endothelial mitochondria throughout the normal brain can be expected to give rise to a low baseline signal in TSPO molecular imaging studies. Finally, our study emphasises the need for valid and methodologically robust verification of the selectivity of TSPO ligands through the use of TSPO knockout tissues.

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Section: Discussionmentioning

confidence: 99%

Cellular Sources and Regional Variations in the Expression of the Neuroinflammatory Marker Translocator Protein (TSPO) in the Normal Brain

Betlazar

Harrison-Brown

Middleton

et al. 2018

IJMS

111

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“…63 However, studies of TSPO knockout mice under normal physiological conditions did not reveal overt phenotype alterations in steroid metabolism. [59][60][61][62] These observations require confirmation in TSPO knockout mice under conditions of physiological stress, where steroid homeostasis may be perturbed.…”

Section: Tspo Functionmentioning

confidence: 99%

Sifting through the surfeit of neuroinflammation tracers

Cumming

Burgher

Patkar

et al. 2017

J Cereb Blood Flow Metab

113

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The first phase of molecular brain imaging of microglial activation in neuroinflammatory conditions began some 20 years ago with the introduction of [C]-( R)-PK11195, the prototype isoquinoline ligand for translocator protein (18 kDa) (TSPO). Investigations by positron emission tomography (PET) revealed microgliosis in numerous brain diseases, despite the rather low specific binding signal imparted by [C]-( R)-PK11195. There has since been enormous expansion of the repertoire of TSPO tracers, many with higher specific binding, albeit complicated by allelic dependence of the affinity. However, the specificity of TSPO PET for revealing microglial activation not been fully established, and it has been difficult to judge the relative merits of the competing tracers and analysis methods with respect to their sensitivity for detecting microglial activation. We therefore present a systematic comparison of 13 TSPO PET and single photon computed tomography (SPECT) tracers belonging to five structural classes, each of which has been investigated by compartmental analysis in healthy human brain relative to a metabolite-corrected arterial input. We emphasize the need to establish the non-displaceable binding component for each ligand and conclude with five recommendations for a standard approach to define the cellular distribution of TSPO signals, and to characterize the properties of candidate TSPO tracers.

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“…This led to the change in nomenclature from "peripheral benzodiazepine receptor" to "translocator protein" [40]. However, sparked by the creation of global TSPO knockout mouse models from independent groups [41][42][43][44], in which mice displayed normal pregnenolone levels, an overall shift in thinking about the functioning of TSPO emerged (several reviews exist which detail the history of TSPO research more comprehensively [45][46][47]). The field of TSPO has since expanded into several different pathways, with many of these lines of enquiry converging on the primary role of TSPO in immunomodulation, cellular bioenergetics, and associated mitochondrial processes.…”

Section: Introductionmentioning

confidence: 99%

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Betlazar

Middleton

Bánati

et al. 2020

Cells

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The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.

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Global Deletion of TSPO Does Not Affect the Viability and Gene Expression Profile

Cited by 34 publications

References 49 publications

Cellular Sources and Regional Variations in the Expression of the Neuroinflammatory Marker Translocator Protein (TSPO) in the Normal Brain

Cellular Sources and Regional Variations in the Expression of the Neuroinflammatory Marker Translocator Protein (TSPO) in the Normal Brain

Sifting through the surfeit of neuroinflammation tracers

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

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