Human Molecular Genetics Advance Access published online on October 3, 2007
Human Molecular Genetics, 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 Dept. of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK 3 Dept. of Experimental Medicine, University of Genoa, IFOM Center of Cell Oncology and Ultrastructure, Genoa, Italy 4 MicroSCoBiO Research Center, University of Genoa, and IFOM Center of Cell Oncology and Ultrastructure, Genoa, Italy 5 Medical Genetics, Dept. of Pediatrics, Federico II University, Naples, Italy
Correspondence to: Prof. Andrea Ballabio Telethon Institute of Genetics and Medicine (TIGEM) Via P. Castellino 111 80131 Napoli, Italy Phone: +39-081-6132207 FAX: +39-081-5790919 ballabio{at}tigem.it
Received August 5, 2007; Revised September 30, 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.
* Both DCR and AB should be regarded as senior authors
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