title: A block of autophagy in lysosomal storage disorders.
abstract: 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.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fraldi
authors.forename: Luca
authors.initials: L
authors.lastname: Jahreiss
authors.forename: Carmine
authors.initials: C
authors.lastname: Spampanato
authors.forename: Consuelo
authors.initials: C
authors.lastname: Venturi
authors.forename: Diego
authors.initials: D
authors.lastname: Medina
authors.forename: Raquel
authors.initials: R
authors.lastname: de Pablo
authors.forename: Carlo
authors.initials: C
authors.lastname: Tacchetti
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D020140:Lysosomal Storage Diseases, Nervous System / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008247:Lysosomes / Q000473:pathology; D008561:Membrane Fusion; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology; D009084:Mucopolysaccharidosis III / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D052517:Multiple Sulfatase Deficiency Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010588:Phagosomes / Q000473:pathology; D014162:Transfection; D054875:Ubiquitination
chemical_list: D017931:DNA Primers; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins