Human Molecular Genetics Advance Access originally published online on October 3, 2007
Human Molecular Genetics 2008 17(1):119-129; doi:10.1093/hmg/ddm289
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A block of autophagy in lysosomal storage disorders
1 Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy 2 Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK 3 Department of Experimental Medicine and 4 MicroSCoBiO Research Center and IFOM Center of Cell Oncology and Ultrastructure, University of Genoa, Genoa, Italy 5 Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy
* To whom correspondence should be addressed at: Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Napoli, Italy. Tel: +39 0816132207; Fax: +39 0815790919; Email: ballabio{at}tigem.it
Received August 5, 2007; Accepted September 30, 2007
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Both D.C.R. and A.B. should be regarded as senior authors.
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