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Cell Death Dis. 2017 Jan 19;8(1):e2565. doi: 10.1038/cddis.2016.475.

Autophagy dysregulation in Danon disease.

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Department of Neurosciences, Biomedical Campus Pietro d'Abano, University of Padova, Padova, Italy.
Institut Necker Enfant-Malades (INEM), INSERM U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
Fondazione IRCCS San Camillo Hospital, Venice, Italy.
Venetian Institute of Molecular Medicine, Padova, Italy.
Department of Biomedical Science, Venetian Institute of Molecular Medicine (VIMM), University of Padova, Padova, Italy.


The autophagy-lysosome system is critical for muscle homeostasis and defects in lysosomal function result in a number of inherited muscle diseases, generally referred to as autophagic vacuolar myopathies (AVMs). Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects. DD is characterized by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The DD mouse model suggests that inefficient lysosome biogenesis/maturation and impairment of autophagosome-lysosome fusion contribute to the pathogenesis of muscle wasting. To define the role of autophagy in human disease, we analyzed the muscle biopsies of DD patients and monitored autophagy and several autophagy regulators like transcription factor EB (TFEB), a master player in lysosomal biogenesis, and vacuolar protein sorting 15 (VPS15), a critical factor for autophagosome and endosome biogenesis and trafficking. Furthermore, to clarify whether the mechanisms involved are shared by other AVMs, we extended our mechanistic study to a group of adult GSDII patients. Our data show that, similar to GSDII, DD patients display an autophagy block that correlates with the severity of the disease. Both DD and GSDII show accumulation and altered localization of VPS15 in autophagy-incompetent fibers. However, TFEB displays a different pattern between these two lysosomal storage diseases. Although in DD TFEB and downstream targets are activated, in GSDII patients TFEB is inhibited. These findings suggest that these regulatory factors may have an active role in the pathogenesis of these diseases. Therapeutic approaches targeted to normalize these factors and restore the autophagic flux in these patients should therefore be considered.

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