A block of autophagy in lysosomal storage disorders

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 ly...

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Vydané v:	Human molecular genetics Ročník 17; číslo 1; s. 119
Hlavní autori:	Settembre, Carmine, Fraldi, Alessandro, Jahreiss, Luca, Spampanato, Carmine, Venturi, Consuelo, Medina, Diego, de Pablo, Raquel, Tacchetti, Carlo, Rubinsztein, David C, Ballabio, Andrea
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England 01.01.2008
Predmet:	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
ISSN:	0964-6906
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0964-6906
DOI:	10.1093/hmg/ddm289