Mucopolysaccharidosis and Autophagy: Controversies on the Contribution of the Process to the Pathogenesis and Possible Therapeutic Applications

Abstract

Mucopolysaccharidosis (MPS) consists of a group of 11 enzymatic defects which result in accumulation of undegraded glycosaminoglycans (GAG) in lysosomes. MPS is a severe metabolic disease for which only bone marrow/hematopoietic stem cell transplantation and enzyme replacement therapy are current therapeutic options. However, they are available for only a few of MPS types, and are ineffective in treatment of central nervous system. Recent studies indicated that the autophagy process can be impaired in MPS, but various contradictory conclusions have been published in this matter. Nevertheless, stimulation of autophagy has been proposed as a potential therapeutic option for MPS, and very recent results suggest that such approach might be effective in improving MPS symptoms. Still the mechanisms of autophagy changes in MPS are not clear, and efficiency of autophagy activation in clearing the storage material requires further investigation. These problems are summarized and discussed in this review.

Keywords: Autophagy; Genistein; Glycosaminoglycans; Mucopolysaccharidosis; Trehalose.

Fig. 1

The scheme of the possible influence of mucopolysaccharidosis (MPS) on autophagy, and a proposal for autophagy activation as a therapeutic strategy for MPS treatment. Mucopoilysaccharidosis (MPS) is a group of inherited metabolic diseases caused by impaired degradation and resultant accumulation of glycosaminoglycans in lysosomes (right panel). This accumulation leads to dysfunction of lysosomes and possible (question mark) impairment of the autophagy process (left panel). Activation of autophagy can be considered (question mark) as a therapeutic strategy for MPS, as enhanced degradation of primary and/or secondary storage material might restore cellular functions. This approach could be particularly useful in treatment of neuronopathic forms of MPS, where no effective therapy for central nervous system symptoms is currently available