• Open Access

Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease

Authors

  • Carmine Spampanato,

    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
    2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    3. Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA
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    • Spampanato and Feeney contributed equally as the two co-first authors.

  • Erin Feeney,

    1. Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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    • Spampanato and Feeney contributed equally as the two co-first authors.

  • Lishu Li,

    1. Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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    • Li, Cardone, Lim, and Annunziata contributed equally among themselves.

  • Monica Cardone,

    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
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    • Li, Cardone, Lim, and Annunziata contributed equally among themselves.

  • Jeong-A Lim,

    1. Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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    • Li, Cardone, Lim, and Annunziata contributed equally among themselves.

  • Fabio Annunziata,

    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
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    • Li, Cardone, Lim, and Annunziata contributed equally among themselves.

  • Hossein Zare,

    1. Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Roman Polishchuk,

    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
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  • Rosa Puertollano,

    1. Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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  • Giancarlo Parenti,

    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
    2. Department of Pediatrics, Federico II University, Naples, Italy
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  • Andrea Ballabio,

    Corresponding author
    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
    2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    3. Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA
    4. Department of Pediatrics, Federico II University, Naples, Italy
    • Andrea Ballabio, Tel: +39 081 613 2207; Fax: +39 081 579 0919

      Nina Raben, Tel: +1 301 496 1474; Fax: +1 301 480 63 67

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  • Nina Raben

    Corresponding author
    1. Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
    • Andrea Ballabio, Tel: +39 081 613 2207; Fax: +39 081 579 0919

      Nina Raben, Tel: +1 301 496 1474; Fax: +1 301 480 63 67

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Abstract

A recently proposed therapeutic approach for lysosomal storage disorders (LSDs) relies upon the ability of transcription factor EB (TFEB) to stimulate autophagy and induce lysosomal exocytosis leading to cellular clearance. This approach is particularly attractive in glycogen storage disease type II [a severe metabolic myopathy, Pompe disease (PD)] as the currently available therapy, replacement of the missing enzyme acid alpha-glucosidase, fails to reverse skeletal muscle pathology. PD, a paradigm for LSDs, is characterized by both lysosomal abnormality and dysfunctional autophagy. Here, we show that TFEB is a viable therapeutic target in PD: overexpression of TFEB in a new muscle cell culture system and in mouse models of the disease reduced glycogen load and lysosomal size, improved autophagosome processing, and alleviated excessive accumulation of autophagic vacuoles. Unexpectedly, the exocytosed vesicles were labelled with lysosomal and autophagosomal membrane markers, suggesting that TFEB induces exocytosis of autophagolysosomes. Furthermore, the effects of TFEB were almost abrogated in the setting of genetically suppressed autophagy, supporting the role of autophagy in TFEB-mediated cellular clearance.

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