Insight into the Structural Features of TSPO: Implications for Drug Development

Lacapère, J; Duma, Luminita; Finet, Stéphanie; Kassiou, Michael; Papadopoulos, Vassilios

doi:10.1016/j.tips.2019.11.005

Cited by 24 publications

(33 citation statements)

References 88 publications

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“…The drug ligand binding domains of TSPO have been mapped [87] and it was subsequently shown that TSPO is a highaffinity cholesterol binding protein containing a conserved cholesterol recognition amino acid consensus domain in the C-terminus [88,89]. The drug and cholesterol binding domains were found to be in distinct domains of the protein results confirmed by NMR [87,88,90].…”

Section: Molecular Structure and Cellular Functionsmentioning

confidence: 91%

Cellular sources of TSPO expression in healthy and diseased brain

Nutma

Ceyzériat

Amor

et al. 2021

Eur J Nucl Med Mol Imaging

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115

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The 18 kDa translocator protein (TSPO) is a highly conserved protein located in the outer mitochondrial membrane. TSPO binding, as measured with positron emission tomography (PET), is considered an in vivo marker of neuroinflammation. Indeed, TSPO expression is altered in neurodegenerative, neuroinflammatory, and neuropsychiatric diseases. In PET studies, the TSPO signal is often viewed as a marker of microglial cell activity. However, there is little evidence in support of a microglia-specific TSPO expression. This review describes the cellular sources and functions of TSPO in animal models of disease and human studies, in health, and in central nervous system diseases. A discussion of methods of analysis and of quantification of TSPO is also presented. Overall, it appears that the alterations of TSPO binding, their cellular underpinnings, and the functional significance of such alterations depend on many factors, notably the pathology or the animal model under study, the disease stage, and the involved brain regions. Thus, further studies are needed to fully determine how changes in TSPO binding occur at the cellular level with the ultimate goal of revealing potential therapeutic pathways.

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Section: Molecular Structure and Cellular Functionsmentioning

confidence: 91%

Cellular sources of TSPO expression in healthy and diseased brain

Nutma

Ceyzériat

Amor

et al. 2021

Eur J Nucl Med Mol Imaging

Self Cite

110

115

View full text Add to dashboard Cite

show abstract

“…Structural studies of bacterial TSPO showed that PPIX binds to the same site to which PK 11195 binds [Guo et al, 2015;Li et al, 2015]. The binding cavity changes to adapt to various ligand [Lacapere et al, 2019]. It has been described that ALA has a very low affinity for TSPO1 in the millimolar range In the cytosol, the cyclic tetrapyrrole, coproporphyrinogen III, is formed from ALA in a series of four enzymatic reactions.…”

Section: Discussionmentioning

confidence: 99%

TSPO2 translocates 5‐aminolevulinic acid into human erythroleukemia cells

Manceau

Lefevre

Mirmiran

et al. 2020

Biology of the Cell

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Background. 5-Aminolevulinic acid (ALA) is the first precursor of heme biosynthesis pathway. The exogenous addition of ALA to cells leads to protoporphyrin IX (PPIX) accumulation that has been exploited in photodynamic diagnostic and photodynamic therapy. Several types of ALA transporters have been described depending on the cell type, but there was no clear entry pathway for erythroid cells. The 18 kDa translocator protein (TSPO) has been proposed to be involved in the transport of porphyrins and heme analogs.Results. ALA-induced PPIX accumulation in erythroleukemia cells (UT-7 and K562) was impaired by PK 11195, a competitive inhibitor of both transmembrane proteins TSPO (1 and 2). PK 11195 did not modify the activity of the enzymes of heme biosynthesis, suggesting that ALA entry at the plasma membrane was the limiting factor. In contrast, porphobilinogen (PBG)-induced PPIX accumulation was not affected by PK 11195, suggesting that plasma membrane TSPO2 is a selective transporter of ALA. Overexpression of TSPO2 at the plasma membrane of erythroleukemia cells increased ALA-induced PPIX accumulation, confirming the role of TSPO2 in the import of ALA into the cells.Conclusions. ALA-induced PPIX accumulation in erythroid cells involves TSPO2 as a selective translocator through the plasma membrane.Significance. This is the first characterisation of molecular mechanisms involving a new actor in ALA transport in ALA-induced PPIX accumulation in erythroleukemia cells, which could be inhibited by specific drug ligands.Additional supporting information may be found online in the Supporting Information section at the end of the article.

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“…Improved insights into the key structural features of TSPO that influence ligand binding and its function under pathological conditions will also guide medicinal chemists in their attempts to rationally design drugs that have potent and predictable neuroprotective effects. [65] For those of us focusing our efforts on targeting TSPO, there are undoubtedly more adventures ahead.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Adventures in Translocation: Studies of the Translocator Protein (TSPO) 18 kDa

Danon

Tregeagle²,

Kassiou³

2021

Aust. J. Chem.

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The 18 kDa translocator protein (TSPO) is an evolutionarily conserved transmembrane protein found embedded in the outer mitochondrial membrane. A secondary target for the benzodiazepine diazepam, TSPO has been a protein of interest for researchers for decades, particularly owing to its well-established links to inflammatory conditions in the central and peripheral nervous systems. It has become a key biomarker for assessing microglial activation using positron emission tomography (PET) imaging in patients with diseases ranging from atherosclerosis to Alzheimer's disease. This Account describes research published by our group over the past 15 years surrounding the development of TSPO ligands and their use in probing the function of this high-value target.

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Insight into the Structural Features of TSPO: Implications for Drug Development

Cited by 24 publications

References 88 publications

Cellular sources of TSPO expression in healthy and diseased brain

Cellular sources of TSPO expression in healthy and diseased brain

TSPO2 translocates 5‐aminolevulinic acid into human erythroleukemia cells

Adventures in Translocation: Studies of the Translocator Protein (TSPO) 18 kDa

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