Mucolipidosis type IV: the importance of functional lysosomes for efficient autophagy.

Mucolipidosis IV (MLIV) is a lysosomal storage disorder characterized by severe neurological and ophthalmologic abnormalities. In contrast with most lysosomal storage disorders, which are attributed to the absence of specific lysosomal hydrolases, accumulation of material in MLIV results from defects in membrane transport along the late endocytic pathway. Mutations in MCOLN1 are the cause of MLIV; however, how the lack of MCOLN1 function ultimately leads to neurodegeneration remains largely unknown. We found that MCOLN1 is required for efficient fusion of both late endosomes and autophagosomes with lysosomes. Impaired autophagosome degradation results in accumulation of autophagosomes in MLIV fibroblasts. In addition, we found increased levels and aggregation of p62, suggesting that abnormal accumulation of ubiquitinated protein inclusions may contribute to the neurodegenerative phenotype observed in MLIV patients. These findings corroborate recent evidence indicating that defects in autophagy may be a common feature of many neurodegenerative disorders.