Abnormal autophagy, ubiquitination, inflammation and apoptosis are dependent upon lysosomal storage and are useful biomarkers of mucopolysaccharidosis VI

BACKGROUND Lysosomal storage diseases are characterized by intracellular accumulation of metabolites within lysosomes. Recent evidence suggests that lysosomal storage impairs autophagy resulting in accumulation of polyubiquitinated proteins and dysfunctional mitochondria, ultimately leading to apoptosis. We studied the relationship between lysosome storage and impairment of different intracellular pathways and organelle function in mucopolysaccharidosis VI, which is characterized by accumulation of dermatan sulfate and signs of visceral and skeletal but not cerebral involvement. RESULTS We show lysosomal storage, impaired autophagy, accumulation of polyubiquitinated proteins, and mitochondrial dysfunction in fibroblasts from mucopolysaccharidosis VI patients. We observe similar anomalies, along with inflammation and cell death, in association with dermatan sulfate storage in the visceral organs of mucopolysaccharidosis VI rats, but not in their central nervous system where dermatan sulfate storage is absent. Importantly, we show that prevention of dermatan sulfate storage in the mucopolysaccharidosis VI rat visceral organs by gene transfer results in correction of abnormal autophagy, inflammation, and apoptosis, suggesting that dermatan sulfate accumulation impairs lysosomal ability to receive and degrade molecules and organelles from the autophagic pathway, thus leading to cell toxicity. CONCLUSION These results indicate that the non-lysosomal degradation pathways we found activated in mucopolysaccharidosis VI can be both targets of new experimental therapies and biomarkers for follow-up of existing treatments.