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Autophagy dysregulation in Danon disease
#MMPMID28102838
Nascimbeni AC
; Fanin M
; Angelini C
; Sandri M
Cell Death Dis
2017[Jan]; 8
(1
): e2565
PMID28102838
show ga
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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