Abstract
The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is expressed in the injured brain. It has become known as an imaging marker of “neuroinflammation” indicating active disease, and is best interpreted as a nondiagnostic biomarker and disease staging tool that refers to histopathology rather than disease etiology. The therapeutic potential of TSPO as a drug target is mostly based on the understanding that it is an outer mitochondrial membrane protein required for the translocation of cholesterol, which thus regulates the rate of steroid synthesis. This pivotal role together with the evolutionary conservation of TSPO has underpinned the belief that any loss or mutation of TSPO should be associated with significant physiological deficits or be outright incompatible with life. However, against prediction, full Tspo knockout mice are viable and across their lifespan do not show the phenotype expected if cholesterol transport and steroid synthesis were significantly impaired. Thus, the “translocation” function of TSPO remains to be better substantiated. Here, we discuss the literature before and after the introduction of the new nomenclature for TSPO and review some of the newer findings. In light of the controversy surrounding the function of TSPO, we emphasize the continued importance of identifying compounds with confirmed selectivity and suggest that TSPO expression is analyzed within specific disease contexts rather than merely equated with the reified concept of “neuroinflammation.”
Highlights
Active brain disease causes a change in the functional state of microglia
The new nomenclature was argued for on several grounds: (i) the transport, or “translocation” of cholesterol as the preeminent role of the protein over alternative functions, notably in energy metabolism [77, 133, 182]; (ii) the sequence homology with the tryptophan-rich sensory protein family (TspO) that function as light, oxygen and stresssensitive regulators of photosynthesis genes; and (iii) the applicability of the name “translocator protein (TSPO)” across species, noting that the rat gene had been shown to substitute for its Rhodobacter sphaeroides homolog TspO [182]
An important first study that explored this was that by Papadopoulos et al [138], which measured the production of progesterone in MA-10 Leydig cells in the presence of known TSPO ligands including the isoquinoline carboxamides PK11195, PK14067, PK14068, as well as the benzodiazepines Ro5-4864, diazepam, flunitrazepam, clonazepam, zolpidem and flumazenil at a range of concentrations
Summary
Active brain disease causes a change in the functional state of microglia This state change is associated with the de novo expression of the mitochondrial 18 kDa translocator protein (TSPO; or peripheral benzodiazepine receptor; PBR), a binding site for which selective high-affinity compounds were developed in the early 1980s [27, 99,100,101]. This discovery was the starting point for the systematic development of in vivo imaging of cellular (nonneuronal) brain pathology (Figure 1). Like the “neuroinflammation” concept, the concept of “translocation” is critically dependent on the context within which it is applied
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