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Altered Gene Expression in Cells from Patients with Lysosomal Storage Disorders Suggests Impairment of the Ubiquitin Pathway

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Altered Gene Expression in Cells from Patients with Lysosomal Storage Disorders Suggests Impairment of the Ubiquitin Pathway Cell Death and Differentiation (2007) 14, 511–523 & 2007 Nature Publishing Group All rights reserved 1350-9047/07 $30.00 www.nature.com/cdd Altered gene expression in cells from patients with lysosomal storage disorders suggests impairment of the ubiquitin pathway P Bifsha1, K Landry1, L Ashmarina1, S Durand1, V Seyrantepe1, S Trudel1, C Quiniou1, S Chemtob1,YXu2, RA Gravel2, R Sladek3 and AV Pshezhetsky*,1 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. Cell Death and Differentiation (2007) 14, 511–523. doi:10.1038/sj.cdd.4402013; published online 4 August 2006 A genetically determined deficiency of lysosomal enzymes antiubiquitin immunoreactivity in contrast to the cells of normal and proteins, or of proteins involved in lysosomal biogenesis, controls.1 The cells of animal models of MPS VII,2 Niemann- results in lysosomal storage disorders (LSD), characterized Pick disease3 and prosaposin deficiency4 also contain by the accumulation of partially undegraded catabolic ubiquitinated protein aggregates. Monoubiquitination is now products in the lysosomes leading to their increased size considered one of the major signals that targets transmem- and number. This severely affects cell turnover causing brane proteins for lysosomal degradation (reviewed in malfunction of many tissues and organs, and in particular Bonifacino and Traub5), but the mechanism relating lysoso- leads to hepatosplenomegaly, corneal clouding, skeletal mal storage and formation of ubiquitinated aggregates is not deformation and central nervous system degeneration. understood. Although rapid progress has been achieved in revealing the Another common feature among different classes of LSD is genetic basis of many LSD, much less is known about the the increased occurrence of cell death. For example, high mechanisms underlying the disruption of cell metabolic and levels of apoptosis were detected in neurons, microglia and signalling pathways associated with these conditions. Despite Purkinje cells of patients affected with Tay-Sachs disease, the broad variability of LSD, diseases that store similar types Globoid cell leukodystrophy (Krabbe disease), Nieman-Pick of macromolecules (sphingolipids, mucopolisaccharides or disease type C, GM1-gangliosidosis, Gaucher disease and glycoproteins) often have similar biochemical, pathological infantile neuronal ceroid lipofuscinosis.6–12 In addition, apop- and clinical phenotypes, suggesting that the nature and tosis of cartilage cells (chondrocytes) was detected in distribution of the stored material is the major lesion-defining mucopolysaccharidosis (MPS) Type VI,13 while apoptosis of factor. However, some cellular pathological features are muscle cells leading to loss of cardiac muscle mass and common even between different major classes of LSD. For cardiomyopathy was found in Pompe disease.14 Apoptosis example, in many cases lysosomal storage is accompanied was also observed in cultured cells of LSD patients, including by the appearance of ubiquitinated protein aggregates. fibroblasts and renal tubular epithelial cells from patients Previous studies have demonstrated that 20–30% of small affected with cystinosis.15 In several cases, accumulated and motor neurons of patients affected with Tay-Sachs substrates of the deficient enzymes (such as psychosine in disease, Niemann-Pick disease and Hunter disease showed globoid cell leukodystrophy, or ceramide in Farber disease) 1Sainte-Justine Hospital and Departments of Pediatrics and Biochemistry, University of Montreal, Montreal, Canada; 2Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada and 3Department of Genetics, McGill University and Genome Quebec Innovation Centre, Montre´al, Que´bec, Canada *Corresponding author: AV Pshezhetsky, Service de ge´ne´tique me´dicale, Hoˆpital Sainte-Justine, 3175 Coˆte Ste-Catherine, Montre´al, Canada Qc H3T 1C5. Tel: þ 1 514 345 4931/2736; Fax: þ 1 514 345 4766; E-mail: [email protected] Keywords: apoptosis; lysosomal storage disorders; proteosome; RNA arrays; Sandhoff disease; ubiquitin C-terminal hydrolase Abbreviations: UCH-L1, ubiquitin C-terminal hydrolase 1; LSD, lysosomal storage disorders; MPS, mucopolysaccharidosis; SIASD, sialic acid storage disease; HEXB, lysosomal hexosaminidase B; LC, liquid chromatography; MS/MS, tandem mass spectroscopy; E-64, epoxysuccinyl-leucylamido-(4-guanidino) butane; LAMP-2, lysosome-associated membrane protein 2; GAD, gracile axonal dystrophy; mUb, monoubiquitin Received 03.8.05; revised 26.5.06; accepted 13.6.06; Edited by RA Knight; published online 04.8.06 Lysosomal storage suppresses ubiquitin pathway P Bifsha et al 512 were shown to be directly cytotoxic and to induce apoptosis shown for GM1-gangliosidosis, Morquio B disease, sialidosis 16 (reviewed by Tardy et al. ). In other LSD, such as GM2- and and galactosialidosis (Hinek A., private communication). GM1-gangliosidoses and mucopolysaccharidoses I and IIIB, On the other hand, the majority of differentially regulated central nervous system apoptosis resulted from general transcripts identified in our microarray studies have not been inflammation (see for example Wada et al.17 and Mizukami previously reported in association with LSD (Table 1). This et al.18). Although there are examples of LSD not accom- latter group includes ubiquitin C-terminal hydrolase L1 (UCH- panied by increased cell death, these data suggest that L1), a member of the deubiquitinating enzyme family apoptosis is a frequent event. presumably involved in ubiquitin recycling to maintain the In this study, we investigated the link between impairment of pool of monomeric ubiquitin in the cell. Malfunction of the the ubiquitin-dependent protein degradation pathway and the ubiquitin pathway due to the UCH-L1 deficiency has pre- increased occurrence of programmed cell death in different viously been associated with neuronal degeneration in a small classes of LSD. We evaluated the secondary changes in the number of patients with autosomal dominant Parkinson’s transcriptome and the proteome of cultured skin fibroblasts disease (PARK5).19 As neuronal death and dystrophy is also from normal individuals and from LSD patients and observed a characteristic feature in LSD, we wished to further that major ubiquitin C-terminal hydrolase, UCH-L1, was characterize the relationship between decreased UCH-L1 downregulated in the cells of eight different lysosomal expression and LSD. disorders, as well as in the brain of a mouse model of Sandhoff disease. We also showed that the inhibition of Expression of UCHL-1 in fibroblasts of patients affected lysosomal catabolism caused secondary deficiency of UCH- with LSD. In order to confirm the suppression of UCH-L1 L1 and that downregulation of UCH-L1 directly induced expression detected by the microarray experiments and to caspase-mediated apoptosis. Taken together, our data determine if the UCH-L1 expression was altered in cell lines suggest that the UCH-L1 deficiency and impairment of the obtained from patients affected with other LSD, we analyzed ubiquitin-dependent protein degradation pathway can con- the level of UCH-L1 mRNA by real-time PCR in the cultured tribute to increased cell death in LSD. skin fibroblasts from five different healthy controls and from 11 patients affected with the following LSD: SIASD (1 line), sialidosis (2 lines), galactosialidosis (1 line), GM1- Results gangliosidosis (2 lines), Morquio syndrome type A (1 line) and B (2 lines), and Gaucher disease (types I and II, one line Secondary changes in the RNA expression patterns in each). These experiments (Figure 1a) demonstrated that the the cells of LSD patients. To identify genes whose level of UCH-L1 mRNA in the affected cell lines was expression was altered by the presence of lysosomal significantly reduced (mean 23.5%, median 23% of normal) storage products, we used oligonucleotide microarrays to compared to an internal control (18S mRNA, data not compare mRNA transcript levels in cultured skin fibroblasts shown). from normal individuals with those of fibroblasts obtained The results of these expression studies were confirmed by from patients affected with sialic acid storage disease several biochemical experiments. We performed immuno- (SIASD) or sialidosis. Although these conditions are caused histochemical staining of UCH-L1 in normal fibroblasts and in by different primary genetic defects and result in the the fibroblasts from the LSD patients. Anti-UCH-L1 immuno- accumulation of different storage
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