New targets for old diseases: lessons from mucolipidosis type II

Abstract

Lysosomal storage disorders (LSDs) are inherited diseases characterized by progressive intracellular accumulation of undigested macromolecules within the cell due to specific lysosomal defects. Lysosomal storage results in a global impairment of many lysosome‐dependent pathways ( e.g . autophagy and endocytosis), leading to cellular dysfunction and death (Ballabio & Gieselmann, 2009). LSD patients often have a complex phenotype, with visceral, skeletal, haematological and neurological involvement. Several mechanisms underlie the etiopathogenesis of the LSDs and their relative contribution may vary, depending on the tissue and cell type. For instance, a generalized inflammatory process affecting multiple tissues has been observed in several mouse models of LSDs, although its role in disease pathogenesis remains still largely unclear (Ballabio & Gieselmann, 2009). Over 50 different LSDs have been described to date, which are due to mutations in genes that encode soluble hydrolases, membrane proteins and lysosomal accessory proteins, resulting in the block of a specific catabolic pathway. Among the lysosomal accessory proteins, one notable example is that of the α and β subunits of the N ‐acetylglucosamine phosphotransferase complex, which are encoded by the GNPTAB gene. This complex catalyses the post‐translational incorporation of a mannose 6‐phosphate (M6P) residue on newly synthesized lysosomal enzymes (Bao et al, 1996). This glycosylation event is crucial for the correct M6P receptor‐dependent targeting of lysosomal enzymes to lysosomes (Braulke & Bonifacino, 2009). In patients affected by mucolipidosis type II (MLII), a LSD due to mutations of the GNPTAB gene, lysosomal enzymes are missorted to the extracellular space. This results in intra‐lysosomal deficiency of multiple enzymes and consequent accumulation of undigested substrates in several organs and tissues, particularly the skeletal system. The pathological mechanisms leading from cellular storage defects to skeletal abnormalities in MLII patients (Schweizer et al, 2013) are poorly understood; it is therefore crucial to improve our understanding …