title: Altered gene expression in cells from patients with lysosomal storage disorders suggests impairment of the ubiquitin pathway.
abstract: By comparing mRNA profiles in cultured fibroblasts from patients affected with lysosomal storage diseases, we identified differentially expressed genes common to these conditions. These studies, confirmed by biochemical experiments, demonstrated that lysosomal storage is associated with downregulation of ubiquitin C-terminal hydrolase, UCH-L1 in the cells of eight different lysosomal disorders, as well as in the brain of a mouse model of Sandhoff disease. Induction of lysosomal storage by the cysteine protease inhibitor E-64 also reduced UCH-L1 mRNA, protein level and activity. All cells exhibiting lysosomal storage contained ubiquitinated protein aggregates and showed reduced levels of free ubiquitin and decreased proteasome activity. The caspase-mediated apoptosis in E-64-treated fibroblasts was reversed by transfection with a UCH-L1 plasmid, and increased after downregulation of UCH-L1 by siRNA, suggesting that UCH-L1 deficiency and impairment of the ubiquitin-dependent protein degradation pathway can contribute to the increased cell death observed in many lysosomal storage disorders.
authors.affiliation: Sainte-Justine Hospital, Department of Pediatrics and Biochemistry, University of Montreal, Montreal, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Bifsha
authors.forename: K
authors.initials: K
authors.lastname: Landry
authors.forename: L
authors.initials: L
authors.lastname: Ashmarina
authors.forename: S
authors.initials: S
authors.lastname: Durand
authors.forename: V
authors.initials: V
authors.lastname: Seyrantepe
authors.forename: S
authors.initials: S
authors.lastname: Trudel
authors.forename: C
authors.initials: C
authors.lastname: Quiniou
authors.forename: S
authors.initials: S
authors.lastname: Chemtob
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: R A
authors.initials: RA
authors.lastname: Gravel
authors.forename: R
authors.initials: R
authors.lastname: Sladek
authors.forename: A V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000818:Animals; D017209:Apoptosis; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016464:Lysosomal Storage Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D012313:RNA / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D034741:RNA, Small Interfering; C482860:UCHL1 protein, human; D025801:Ubiquitin; D012313:RNA; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex; D007930:Leucine; C024974:E 64