A block of autophagy in lysosomal storage disorders

Hum Mol Genet. 2008 Jan 1;17(1):119-29. doi: 10.1093/hmg/ddm289. Epub 2007 Oct 3.


Most lysosomal storage disorders (LSDs) are caused by deficiencies of lysosomal hydrolases. While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood. Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion. An impairment of the autophagic pathway was demonstrated by the inefficient degradation of exogenous aggregate-prone proteins (i.e. expanded huntingtin and mutated alpha-synuclein) in cells from LSD mice. This impairment resulted in massive accumulation of polyubiquitinated proteins and of dysfunctional mitochondria which are the putative mediators of cell death. These data identify LSDs as 'autophagy disorders' and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics
  • Autophagy / physiology*
  • Base Sequence
  • Cells, Cultured
  • DNA Primers / genetics
  • Humans
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / pathology*
  • Lysosomal Storage Diseases / physiopathology
  • Lysosomal Storage Diseases, Nervous System / genetics
  • Lysosomal Storage Diseases, Nervous System / pathology
  • Lysosomal Storage Diseases, Nervous System / physiopathology
  • Lysosomes / pathology
  • Membrane Fusion
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / pathology
  • Mucopolysaccharidosis III / genetics
  • Mucopolysaccharidosis III / pathology
  • Mucopolysaccharidosis III / physiopathology
  • Multiple Sulfatase Deficiency Disease / genetics
  • Multiple Sulfatase Deficiency Disease / pathology
  • Multiple Sulfatase Deficiency Disease / physiopathology
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Phagosomes / pathology
  • Transfection
  • Ubiquitination


  • DNA Primers
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins