115 TSPO expression in healthy and diseased brain Introduction The 18 kDa translocator protein (TSPO) is increasingly used as a marker for in vivo neuroinflammation with positron emission tomography (PET) in a wide variety of CNS diseases. Many of these studies reveal that TSPO PET signal is altered in neurodegenerative, neuroinflammatory and neuropsychiatric diseases when compared to healthy individuals1. Historically, TSPO has been viewed as a marker of microglial cell activity. Indeed, the first studies showing a correlation between the binding of one of the TSPO tracers and microglia speculated that TSPO is a marker for pathogenic microglial cells1,2. This idea is no longer maintained. Indeed, the presence of TSPO in other cell types, notably astrocytes and endothelial cells, has been demonstrated3-6. TSPO is not the only molecular target for PET imaging of neuroinflammation. Several other receptors that are expressed in brain cells and are potentially upregulated in neuroinflammation have been identified and specific radiotracers are developed to label them in vivo. For instance, radiotracers binding the cannabinoid receptor 2 (CB2) receptor 7,8 and cyclooxygenase-2 (COX-2)9,10 have been validated in preclinical models of brain disease and generally showed a robust increase in binding associated with neuroinflammation, while the first results from human PET studies are encouraging11,12. In addition, radiotracers binding the purinergic receptor subtype 7 (P2X7)13-15, the sphingosine-1-phosphate receptor 1 (S1PR1)16, reactive oxygen species17, and the colony stimulating factor 1 receptor (CSF1R)18 are at initial stages of preclinical validation. In light of these results, it is clear that TSPO is the most extensively studied molecular target for in vivo PET imaging of neuroinflammation to date. Here we review the cellular sources and functions of TSPO in animal models and humans in health and in CNS diseases. This will contribute to a better understanding of the function of TSPO, the physiology of TSPO expression, and its functional consequences in the human body and the CNS. Furthermore, knowledge about the expression of TSPO in CNS diseases provides insight into expression patterns and its predictive potential in diagnosing CNS diseases and disease progression with TSPO PET. TSPO functions in health TSPO participates in many essential mitochondria-based physiological processes, including metabolism and cellular bioenergetics, mitochondrial respiration, cholesterol transport and steroidogenesis, immunomodulation, porphyrin transport, and heme biosynthesis19-23. It has also been suggested that TSPO may play critical roles in cell proliferation, tumorigenesis, and apoptosis23-25. In order to discern and evaluate the function of any protein, particularly one like TSPO that seems to be multifunctional, one must consider specific characteristics that could provide clues to the possible roles it may play. The characteristics that need to be investigated should include its: (i) tissue, cellular, and subcellular localization, (ii) characteristics and effects of endogenous and exogenous ligands, (iii) molecular structure and cellular functions, (iv) genetics and genetic models, and (v) evolution. Tissue, cellular and subcellular localization TSPO was first characterized for its ability to bind with specificity and high affinity various classes of chemicals such as benzodiazepines, isoquinoline carboxamides, indole acetamides, pyrazolopyrimidines, and aryloxyanilides, as well as endogenous ligands including porphyrins, the endozepine diazepam binding inhibitor19-23,26-32. Radioligand binding and later on
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