Genetic analysis of dTSPO, an outer mitochondrial membrane protein, reveals its functions in apoptosis, longevity, and Aβ42-induced neurodegeneration

Authors

  • Ran Lin,

    1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
    2. Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
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  • Alessia Angelin,

    1. Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
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  • Federico Da Settimo,

    1. Dipartimento di Farmacia, Università di Pisa, Pisa, Italy
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  • Claudia Martini,

    1. Dipartimento di Farmacia, Università di Pisa, Pisa, Italy
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  • Sabrina Taliani,

    1. Dipartimento di Farmacia, Università di Pisa, Pisa, Italy
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  • Shigong Zhu,

    1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
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  • Douglas C. Wallace

    Corresponding author
    1. Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA
    2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    • Correspondence

      Douglas C. Wallace, Ph.D., Michael and Charles Barnett Chair in Pediatric Mitochondrial Medicine and Metabolic Disease, Director, Center of Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Professor of Pathology and Laboratory Medicine, University of Pennsylvania, Colket Translational Research Building, room 6060, 3501 Civic Center Boulevard, Philadelphia, PA 19104-4302, USA. Tel.: +1 267 425 3034; fax: 267 426 0978; e-mail: wallaced1@email.chop.edu

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Summary

The outer mitochondrial membrane (OMM) protein, the translocator protein 18 kDa (TSPO), formerly named the peripheral benzodiazepine receptor (PBR), has been proposed to participate in the pathogenesis of neurodegenerative diseases. To clarify the TSPO function, we identified the Drosophila homolog, CG2789/dTSPO, and studied the effects of its inactivation by P-element insertion, RNAi knockdown, and inhibition by ligands (PK11195, Ro5-4864). Inhibition of dTSPO inhibited wing disk apoptosis in response to γ-irradiation or H2O2 exposure, as well as extended male fly lifespan and inhibited Aβ42-induced neurodegeneration in association with decreased caspase activation. Therefore, dTSPO is an essential mediator of apoptosis in Drosophila and plays a central role in controlling longevity and neurodegenerative disease, making it a promising drug target.

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