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Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders

Key Points

  • The translocator protein (18 kDa) (TSPO) is a five transmembrane domain protein that is localized primarily in the outer mitochondrial membrane and is expressed predominantly in steroid-synthesizing tissues, including the brain.

  • TSPO is involved in the translocation of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in the synthesis of steroids and neurosteroids and one of the most well-characterized functions of this protein.

  • TSPO expression seems to be a sensitive biomarker of brain damage and neurodegeneration, particularly of inflammation and reactive gliosis.

  • In response to injury, TSPO expression is strongly upregulated in the peripheral nervous system in Schwann cells, macrophages and neurons. Increased TSPO ligand binding has also been investigated as a molecular in vivo sensor of neuronal damage and inflammation in patients with neurodegenerative diseases of the central nervous system (CNS) that are characterized by neuronal loss in discrete areas.

  • Cholesterol, porphyrins and endozepines are endogenous ligands of TSPO. Classical synthetic ligands of TSPO include the isoquinoline PK-11195 and the benzodiazepine Ro5-4864. Over the past two decades, various additional TSPO ligands have been developed, which can be subdivided into distinct chemical classes.

  • Most of the TSPO ligands were developed primarily as neuroimaging agents and diagnostic tools for brain inflammation associated with various neuropathological conditions.

  • Certain specific TSPO ligands are under development also for the treatment of various neurological and psychiatric disorders. Possible indications include peripheral neuropathies, neurodegenerative or traumatic processes within the CNS, and psychiatric disorders, especially anxiety disorders.

  • There are ongoing trials with TSPO ligands for the treatment of chemotherapy-induced peripheral neuropathy and as an adjunct treatment in amyotrophic lateral sclerosis. Moreover, clinical studies with various TSPO ligands have been performed in patients suffering from diabetic neuropathy, in healthy volunteers undergoing an experimental anxiety challenge and in patients with generalized anxiety disorder. Etifoxine is available in France for the treatment of adjustment disorder with anxiety.

  • Systematic clinical studies involving prolonged administration and safety monitoring and differential treatment regimens are needed to evaluate the therapeutic potential of TSPO ligands in relation to their putative side-effect profile.

Abstract

The translocator protein (18 kDa) (TSPO) is localized primarily in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central and peripheral nervous system. One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis. TSPO expression may constitute a biomarker of brain inflammation and reactive gliosis that could be monitored by using TSPO ligands as neuroimaging agents. Moreover, initial clinical trials have indicated that TSPO ligands might be valuable in the treatment of neurological and psychiatric disorders. This Review focuses on the biology and pathophysiology of TSPO and the potential of currently available TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders.

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Figure 1: Structure of TSPO, docking with cholesterol and mitochondrial localization.
Figure 2: TSPO expression in the central and peripheral nervous system, and effects of TSPO ligands.
Figure 3: Classes, names and structures of representative TSPO ligands.
Figure 4: Classes, names and structures of representative TSPO ligands.
Figure 5: Neurosteroidogenesis and neurosteroid signalling induced by TSPO ligands.
Figure 6: Neuronal networks targeted by TSPO ligand-induced neurosteroid signalling.

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Acknowledgements

We thank H. Mohler and F. Holsboer for their insightful comments on the work. We acknowledge funding support from a Max Planck Fellow grant to R.R. V.P. was supported by grants from the US National Institutes of Health (ES07747), the Canadian Institutes of Health Research (211,033), and a Canada Research Chair. G.G. was supported by a grant from the Association Française contre les Myopathies (AFM) and by Biocodex, France. D.A. was supported by a Plan Pluriformation (“Peripheral and spinal axonal regeneration”) from the University Paris-Sud 11, France. M.S. is the beneficiary of an Interface Program of the Institut National de la Santé et de la Recherche Médicale and the Assistance Publique-Hôpitaux de Paris, France.

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Authors and Affiliations

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Competing interests

Rainer Rupprecht has been on the Novartis advisory boards and served as a consultant for Novartis for the development of XBD173. The study on XBD173 (see Rupprecht et al. Science 325, 490–493; 2009) has been sponsored by Novartis. Vassilios Papadopoulos is a named inventor on several international patents that pertain to the use of TSPO as well as to the synthesis and use of TSPO drug ligands. These patents have been licensed by Samaritan Pharmaceuticals. V.P. has also served as a consultant for Samaritan Pharmaceuticals, and has received research funding by Beaufour-IPSEN and Samaritan Pharmaceuticals for work pertaining to TSPO. Michael Schumacher has received research funding from Biocodex relating to his work with etifoxine (see Girard et al. Proc. Natl Acad. Sci. USA 105, 20505–20510; 2008).

Supplementary information

Supplementary information S1 (table)

Classes, names, and structures of TSPO ligands. (PDF 646 kb)

Related links

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FURTHER INFORMATION

ClinicalTrials.gov

International Union of Pure and Applied Chemistry (IUPAC)

RCSB Protein Data Bank

SWISS-MODEL

Glossary

Cholesterol

A 27-carbon steroid present in cells and bodily fluids. It is a basic component of membranes and a precursor of steroid hormones, bile acids and vitamins.

Microglia

A type of glial cell that is the resident macrophage in the brain and spinal cord, and the primary mediator of the immune system of the central nervous system.

Reactive astrocytes

In response to injury and degenerative conditions, astrocytes become hypertrophic and extend processes, accompanied by increased expression of surface molecules, neurotrophic factors, hormones and cytokines. They can exert both beneficial and detrimental effects on neuronal survival and axon regeneration.

Mitochondrial permeability transition

(MPT). The increase in the permeability of the mitochondrial membrane to solutes with molecular mass ≤1,500 daltons. It is caused by the opening of the high-conductance permeability transition pore, inducing mitochondrial depolarization, uncoupling of oxidative phosphorylation and swelling, leading to ATP depletion and cell death.

Shape fitting

Shape fitting used in protein docking methods is based on the concept that if a ligand molecule has a similar shape or volume to the binding pocket in a protein, it should overlay well, and any volume mismatch would be a measure of dissimilarity. The fit between the ligand and the binding pocket is based on the matching of both three-dimensional shape and chemical functionalities.

Porphyrins

Heterocyclic compounds formed of four pyrrole rings linked by unsaturated carbons to form a large ring. They can chelate metals such as iron and magnesium, and are crucial constituents of haemoglobin, chlorophyll and cytochromes.

Acyl coenzyme A

(Acyl-CoA). A temporary product formed when coenzyme A attaches to the end of a long-chain fatty acid, which is a step in fatty acid oxidation.

Autocrine and paracrine signalling

During autocrine signalling, a cell secretes a protein and/or a chemical messenger that binds to receptors on the same cell. This differs from paracrine signalling, which targets adjacent cells.

Astrogliosis

The presence of reactive astrocytes.

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Rupprecht, R., Papadopoulos, V., Rammes, G. et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 9, 971–988 (2010). https://doi.org/10.1038/nrd3295

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