Autophagic dysfunction in mucolipidosis type IV patients

• Published in: Human molecular genetics Vol. 17; no. 17; pp. 2723 - 2737
• Main Authors: Vergarajauregui, Silvia, Connelly, Patricia S., Daniels, Mathew P., Puertollano, Rosa
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.09.2008; Oxford Publishing Limited (England)
• Subjects: Autophagy; Biological and medical sciences; Carbohydrates (enzymatic deficiencies). Glycogenosis; Endosomes - metabolism; Errors of metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Lysosomes - metabolism; Medical sciences; Metabolic diseases; Molecular and cellular biology; Mucolipidoses - physiopathology; Receptors, Platelet-Derived Growth Factor - metabolism; Transient Receptor Potential Channels; TRPM Cation Channels - metabolism; Human; Eye disease; Nervous system diseases; Mucolipidosis IV; Metabolic diseases; Genetics; Carbohydrate; Enzymopathy; Genetic disease
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddn174

Mutations in Mucolipin 1 (MCOLN1) have been linked to mucolipidosis type IV (MLIV), a lysosomal storage disease characterized by several neurological and ophthalmological abnormalities. It has been proposed that MCOLN1 might regulate transport of membrane components in the late endosomal–lysosomal pathway; however, the mechanisms by which defects of MCOLN1 function result in mental and psychomotor retardation remain largely unknown. In this study, we show constitutive activation of autophagy in fibroblasts obtained from MLIV patients. Accumulation of autophagosomes in MLIV cells was due to the increased de novo autophagosome formation and to delayed fusion of autophagosomes with late endosomes/lysosomes. Impairment of the autophagic pathway led to increased levels and aggregation of p62, suggesting that abnormal accumulation of ubiquitin proteins may contribute to the neurodegeneration observed in MLIV patients. In addition, we found that delivery of platelet-derived growth factor receptor to lysosomes is delayed in MCOLN1-deficient cells, suggesting that MCOLN1 is necessary for efficient fusion of both autophagosomes and late endosomes with lysosomes. Our data are in agreement with recent evidence showing that autophagic defects may be a common characteristic of many neurodegenerative disorders.