Autophagy dysregulation in Danon disease

Area of Science:

• Cell Biology
• Molecular Biology
• Muscle Physiology

Background:

• The autophagy-lysosome system is vital for muscle health, and its dysfunction leads to inherited muscle diseases known as autophagic vacuolar myopathies (AVMs).
• Danon Disease (DD) results from LAMP2 gene mutations, while glycogen storage disease type II (GSDII) involves primary lysosomal protein defects.
• Dysfunctional autophagy, including impaired autophagosome-lysosome fusion and lysosome biogenesis, contributes to muscle wasting in AVMs.

Purpose of the Study:

• To investigate the role of autophagy and its regulators in human Danon Disease (DD) and glycogen storage disease type II (GSDII).
• To compare the mechanisms underlying muscle pathology in DD and GSDII, focusing on autophagy regulators like TFEB and VPS15.
• To determine if therapeutic strategies targeting autophagy regulators could restore autophagic flux in these muscle diseases.

Main Methods:

• Analysis of muscle biopsies from DD and GSDII patients.
• Monitoring of autophagy markers and regulators, including transcription factor EB (TFEB) and vacuolar protein sorting 15 (VPS15).
• Assessment of VPS15 localization and TFEB activity in relation to disease severity.

Main Results:

• DD and GSDII patients exhibit an autophagy block that correlates with disease severity.
• Accumulation and altered localization of VPS15 were observed in autophagy-incompetent muscle fibers in both DD and GSDII.
• TFEB was activated in DD patients but inhibited in GSDII patients, indicating differential regulation between these diseases.

Conclusions:

• Autophagy dysfunction plays a significant role in the pathogenesis of Danon Disease and glycogen storage disease type II.
• VPS15 accumulation and altered localization, along with differential TFEB activity, are key features of these AVMs.
• Targeting autophagy regulators to restore autophagic flux presents a potential therapeutic avenue for patients with DD and GSDII.