FOR 2858:  Role of translocator protein (18 kDa) (TSPO) as a diagnostic and therapeutic target in the nervous system

• Subject Area: Medicine ; Biology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403161218

TSPO mediates numerous functions such as cholesterol transport, steroidogenesis, and mitochondrial bioenenergetics. Moreover, it plays a role in neurodegeneration, neoplasia, inflammation, and modulation of stress and anxiety. This interdisciplinary research unit formed by scientists from the University Regensburg, the LMU Munich and the DZNE Göttingen aims to unravel the physiology and pathophysiology of TSPO for nervous system disorders and to promote TSPO as a diagnostic and therapeutic target. It is organized into three scientific areas. Area A addresses PET imaging and concomittant tissue analyses in gliomas, area B is dedicated to structure and function of the TSPO molecule, whereas area C focusses on the therapeutic potential of TSPO ligands. During the first funding period, we showed within area A that TSPO PET is indeed of prognostic value in glioma patients and that both tumor and microglia cells contribute to the TSPO PET signal. Moreover, we revealed that TSPO enhances immune escape in glioblastoma. Within area B, we obtained first power spectra of human TSPO and showed that TSPO expression determines a variety of mitochondrial functions. Within area C, we detected that TSPO ligands exert neuroregenerative effects in sensory and motoneurons and that these ligands protect against retinal damage. Moreover, we found that benzodiazepines induce cognitive decline and dendritic spine loss via TSPO. Furthermore, TSPO ligands exerted anxiolytic effects in a gender specific manner in animal models of stress, anxiety and fear. Finally, TSPO ligands differentially modulated neuronal networks when compared with benzodiazpines in an experimental paradigm of stress and anxiety in healthy humans. During the second funding period, projects in area A aim to characterize the prognostic value of TSPO PET for long-term outcome and prognosis in glioma patients and to get a resolution of TSPO PET signals at a single cell level by means of radiotracing. Moreover, the utility of TSPO as a potential target for immunotherapy will be studied. Within area B, we will focus on the interaction of the human TSPO molecule with diagnostic and therapeutic TSPO ligands and on clinically relevant polymorphisms in relation to mitochondrial function. Within area C, we will study the role of TSPO expression and modulation in relation to neurodegeneration and retinal function. Moreover, we will perform translational studies on the role of TSPO expression and modulation in acute and chronic stress conditions regarding behaviour and neuroplasticity. Finally, we will conduct a first clinical proof of concept study in depression as a stress-related disorder to test whether TSPO ligands may constitute a novel class of fast acting antidepressants by promoting endogenous neurosteroidogenesis in relation to modulation of neuronal networks. As such, during the second funding period we aim to delineate the putative clinical potential of TSPO in the nervous system.

• DFG Programme: Research Units
• International Connection: France

Projects

• Architecture and function of the mitochondrial VDAC/TSPO super-complex (Applicants Wetzel, Christian H. ;  Ziegler, Christine Maria )
• Biological functions of glial TSPO in retina and brain models of the cholesterol storage disease Niemann-Pick type C (NPC) (Applicants Grosche, Antje ;  Tahirovic, Ph.D., Sabina )
• C3: The role of TSPO on dendritic spine structural plasticity in health and neurodegenerative diseases (Applicant Herms, Jochen W. )
• Coordination Funds (Applicant Rupprecht, Rainer )
• Differential effects of TSPO ligands on functional connectivity and metabolism related to fear and anxiety in the human brain (Applicants Nothdurfter, Caroline ;  Rupprecht, Rainer ;  Schwarzbach, Jens )
• Histological and molecular characterization of TSPO labeling (Applicants Brendel, Matthias ;  Riemenschneider, Markus J. )
• Interactions of brain TSPO and stress-related systems under acute and chronic stress conditions (Applicants Bosch, Oliver ;  Neumann, Inga D. )
• Neuroprotective and neuroregenerative effects of new TSPO ligands in the peripheral nervous system (Applicant Schumacher, Ph.D., Michael )
• Nuclear magnetic resonance (NMR) spectroscopy of human TSPO (Applicant Zweckstetter, Markus )
• Temporospatial changes of TSPO expression in glioblastoma in response to therapy and during disease progression – a multimodal TSPO PET, amino acid PET, and MRI study (Applicants Albert, Nathalie ;  von Baumgarten, Louisa )
• The role of TSPO expression in neurons, microglia, and the noradrenergic system following acute and chronic stress (Applicants Herms, Jochen W. ;  Paeger, Lars )
• The role of TSPO in T cell immune control of glioblastoma (Applicants Beckhove, Philipp ;  Hau, Peter )
• The role of TSPO in T-cell immune control of glioblastoma (Applicants Beckhove, Philipp ;  Hau, Peter )
• TSPO PET labeling in gliomas as a diagnostic marker in the human brain (Applicants Albert, Nathalie ;  Bartenstein, Peter ;  von Baumgarten, Louisa )

• Spokesperson: Professor Dr. Rainer Rupprecht