- Open Access
Parkin-mediated ubiquitination of mutant glucocerebrosidase leads to competition with its substrates PARIS and ARTS
© Bendikov-Bar et al.; licensee BioMed Central Ltd. 2014
Received: 17 March 2014
Accepted: 28 May 2014
Published: 16 June 2014
Parkinson’s disease (PD) is a movement neurodegenerative disorder characterized by death of dopaminergic neurons in the substantia nigra pars compacta of the brain that leads to movement impairments including bradykinesia, resting tremor, postural instability and rigidity. Mutations in several genes have been associated with familial PD, such as parkin, pink, DJ-1, LRKK2 and α-synuclein. Lately, mutations in the GBA gene were recognized as a major cause for the development of PD.
Mutations in the GBA gene, which encodes for lysosomal β-glucocerebrosidase (GCase), lead to Gaucher disease (GD), an autosomal recessive sphingolipidosis characterized by accumulation of glucosylceramide, mainly in monocyte-derived cells. It is a heterogeneous disease, with Type 1 patients that do not present any primary neurological signs, and Type 2 or Type 3 patients who suffer from a neurological disease. The propensity of type 1 GD patients and carriers of GD mutations to develop PD is significantly higher than that of the non-GD population.
We have shown in the past that parkin and mutant GCase, expressed in heterologous systems, interact with each other, and that normal but not mutant parkin mediates K48-dependent proteasomal degradation of mutant GCase variants.
We tested possible competition between mutant GCase and PARIS or ARTS on the E3 ubiquitin ligase parkin, using coimmunoprecipitation assays and quantitative real-time PCR.
We show that endogenous mutant GCase variants associate with parkin and undergo parkin-dependent degradation. Mutant GCase competes with the known parkin substrates PARIS and ARTS, whose accumulation leads to apoptosis. Dopaminergic cells expressing mutant GCase are more susceptible to apoptotic stimuli than dopaminergic cells expressing normal GCase, present increased cleavage of caspase 3 and caspase 9 levels and undergo cell death.
Our results imply that presence of mutant GCase leads to accumulation of parkin substrates like PARIS and ARTS, which may cause apoptotic death of cells.
Gaucher disease (GD) is an autosomal recessive disease characterized by accumulation of glucosylceramides, mainly in monocyte derived cells. Due to its heterogeneity, it has been divided to Type 1 GD, primarily a non-neurological disease, and Type 2 and 3, two forms associated with a neuronopathic disease [1, 2]. Mutant glucocerebrosidase (GCase) variants undergo ER-associated degradation (ERAD), the degree of which correlates with disease severity . ER-retained mutant GCase leads to ER stress and to unfolded protein response .
There is a significantly higher propensity of GD patients or carriers of GD mutations to develop Parkinson’s disease (PD) compared to the general population [5–19], indicating that not only GD pathology but even the presence of one mutant GBA allele increases the risk for the development of PD.
PD, the second most common neurodegenerative disorder, is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain [20, 21]. It is also associated with the appearance of Lewy bodies (composed of α-synuclein and ubiquitin), depletion of striatal dopamine and gliosis. PD pathology also manifests in non-dopaminergic nerve cells such as olfactory and brain stem neurons, and actually precedes the pathological changes seen in dopaminergic neurons . Motor symptoms in patients, including slowness of movement, resting tremor, rigidity, postural instability and gait difficulty, usually appear after a massive loss of dopamine from the striatum . PD patients may also present non-motor manifestations such as dementia and psychiatric symptoms .
GD is associated with glucosylceramide accumulation and pathogenic presence of mutant GCase, yet it is still unclear whether both contribute to development of PD in GD patients and carriers of GD mutations. One theory suggests a role for glucosylceramide accumulation in α-synuclein aggregation . However, there are no documented reports on accumulation of glucosylceramide in brains of Type 1 GD patients, nor in brains of carriers of GD mutations, raising the possibility that the development of PD in GD patients or in carriers of GD mutations is due to the presence of mutant GCase.
We have shown in the past that mutant GCase undergoes parkin-mediated K48 polyubiquitination and proteasomal degradation. Parkin, a multifunctional RING (Really InterestiNG) domain-containing E3 ubiquitin ligase encoded by the PARK2 gene is a cytoplasmic protein, mutations in which are the most common cause (~50%) of autosomal recessive PD [26, 27]. Parkin regulates diverse functions in the cell, including receptor-mediated trafficking, cell signaling, autophagy and mitochondrial quality control . Parkin regulates receptor-mediated trafficking and signaling through monoubiquitination of substrates . It regulates inclusion body formation and autophagy through lysine 29 and 63 polyubiquitination [30, 31]. Parkin also mediates lysine 48 polyubiquitination of substrates, which are destined to proteasomal degradation [28, 32]. Loss-of-function mutations in the PARK2 gene lead to accumulation of non-cleared lysine-48 substrates. Accumulation of the known parkin substrates PARIS  and ARTS  is pathogenic to cells. Such accumulation was found in post mortem brains of PD patients and in a mouse model of PD mutated in PARK2 , indicating that the loss of parkin function contributes to PD pathogenesis.
In this study we used GD-derived skin fibroblasts to show that endogenous mutant GCase associates with parkin and undergoes parkin-dependent degradation. We utilized human dopaminergic cells in tissue culture to demonstrate competition between mutant GCase and the known parkin substrates PARIS and ARTS, whose accumulation leads to apoptosis of cells.
Material and methods
The following antibodies were used in this study: monoclonal anti-GCase 2E2 (Abnova), generated against a peptide corresponding to amino acids 146–236 of human GCase, rabbit polyclonal anti-GCase, generated against a peptide corresponding to amino acids 517–536 of human GCase (G4171, Sigma), rabbit anti-ERK (C16 Santa Cruz Biotechnology, Santa Cruz, CA, USA), mouse monoclonal anti-actin (MP Biomedicals, OH, USA), mouse monoclonal anti-myc and anti-GFP (Cell Signaling Technology, Beverly, MA, USA); Secondary antibodies: horseradish peroxidase-conjugated goat anti-mouse or goat anti-rabbit (Jackson Immuno Research Laboratories, West Grove, PA, USA), rabbit anti-caspase 3 and rabbit anti-cleaved caspase 9 (Cell Signaling Technology, Beverly, MA, USA).
Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), cyclohexamide (CHX), Leupeptin and phenylmethylsulfonyl fluoride (PMSF) were purchased from Sigma-Aldrich (Rehovot, Israel). Four-methyl-umbelliferyl-glucopyranoside (4-MUG) was purchased from Genzyme Corp (Cambridge, MA, USA). Nonidet P-40 (NP-40) was purchased from Roche Diagnostics (Mannheim, Germany). Absolute Blue qPCR SYBR Green ROX Mix was from TAMAR Laboratory Supplies (Mevaseret Zion, Israel).
Description of cell lines used in the study
Construction of plasmids
Construction of myc-His-GCase plasmids was described elsewhere . pSC2-6myc ARTS was described in . MISSION shRNA plasmid (TRCN0000000285) encoding parkin-targeted shRNA was purchased from Sigma-Aldrich (St Louis, Mo, USA).
To construct the PARIS-expressing vector, a 1.9 kb PARIS cDNA fragment was amplified using Phusion high-fidelity DNA polymerase (New England Biolabs, Ipswich, USA) from the plasmid cFUGW-lenti-PARIS, a kind gift from Dr. Ted M. Dawson (Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA). The PARIS cDNA fragment was cloned into the Ecl136II site of pEGFPC3 vector plasmid (Clontech Laboratories Inc. CA, USA). Gibson assembly technology (New England Biolabs, Ipswich, USA) was used for the cloning. For knockdown of parkin, MISSION short hairpin RNA (shRNA) plasmids, encoding small interfering RNAs (siRNAs) targeting parkin, were purchased from Sigma Aldrich (St Louis, Mo, USA). Of all the existing vectors, TRCN0000000285 successfully knocked down human parkin. As a control, a pLKO.1 plasmid (Sigma Aldrich, St Louis, Mo, USA) harboring shRNA against GFP was used.
Total RNA was isolated using the EZ-RNA kit (Biological Industries, Beit Haemek, Israel), according to the manufacturer’s instructions.
Two micrograms of RNA were reverse transcribed with M-MLV reverse transcriptase (Promega corporation, CA, USA), in the presence of 1 μg oligo-dT primer in a total volume of 20 μl, at 42°C for 60 minutes. Reactions were stopped by incubation at 70°C for 15 minutes. One-two microliters of the resulting cDNA were amplified by quantitative real-time PCR.
Quantitative real-time PCR
One microliter of cDNA was used for real-time PCR. PCR was performed using the KAPA SYBR Fast Universal qPCR kit (Kapa Biosystems, Wilmington, MA, USA) in a Rotor-Gene 6000 (Corbett life sciences, Valencia, CA, USA). The reaction mixture contained 50% qPCR mix, 300 nM of forward primer (5′-ATCTGAAGGAGCAACATCTGG-3′) and 300 nM of reverse primer (5′-CACGGGCGAGTTTACTATGTAG-3′), in a final volume of 10 μl. Thermal cycling conditions were: 95°C (10 minutes), 40 cycles of 95°C (10 seconds), 60°C (20 seconds) and 72°C (20 seconds). Relative gene expression was determined by Ct value.
SDS-PAGE and western blotting
Cell monolayers were washed three times with ice-cold phosphate-buffered saline (PBS) and lysed at 4°C in 500 μl of lysis buffer (10 mM HEPES pH 8.0, 100 mM NaCl, 1 mM MgCl2 and 1% Triton X-100) containing 10 μg/ml aprotinin, 0.1 mM PMSF and 10 μg/ml leupeptin. Lysates were incubated on ice for 30 minutes and centrifuged at 10,000 g for 15 minutes at 4°C. Samples, containing the same amount of protein, were electrophoresed through 10% SDS-PAGE and electroblotted onto a nitrocellulose membrane (Schleicher and Schuell BioScience, Keene, NH, USA). Membranes were blocked with 5% skim milk and 0.1% Tween-20 in Tris-buffered saline (TBS) for 1 hour at room temperature (RT) and incubated overnight with the primary antibody. The membranes were then washed three times in 0.1% Tween-20 in TBS and incubated with the appropriate secondary antibody for 1 hour at RT. After washing, membranes were reacted with ECL detection reagents (Santa Cruz Biotechnology Inc., CA, USA) and analyzed by luminescent image analyzer (X-OMAT 2000 Processor, Kodak, Rochester, NY, USA).
SHSY5Y cells were transfected using either a MP-100 Microporator (Digital Bio Tech, Seoul, South Korea) according to the manufacturer’s instructions, or Lipofectamine 2000™ (Invitrogen, CA, USA).
Subconfluent skin fibroblasts were treated overnight with 25 μM MG-132, after which cells were washed 3 times with ice-cold PBS and lysed at 4°C in 1 ml of lysis buffer (10 mM Hepes pH = 8, 100 mM NaCl, 1 mM MgCl2, and 0.5% NP-40) containing 10 μg/ml aprotinin, 0.1 mM PMSF and 10 μg/ml leupeptin (Sigma-Aldrich, Rehovot, Israel). Following centrifugation at 10,000 g for 15 minutes at 4°C, the supernatants were pre-cleared for 2 hours at 4°C with protein A-agarose (Roche Diagnostic, Mannheim, Germany). Following washes with 1 ml of lysis buffer containing protease inhibitors, proteins were eluted for 10 minutes at 100°C with 5X loading buffer, electrophoresed through 10% SDS-PAGE and blotted. The corresponding blot was interacted with the appropriate antibodies.
Ubiquitination in tissue culture
Sub-confluent skin fibroblasts were treated overnight with 25 μM MG-132, after which stringent immunoprecipitation conditions were applied as previously described , with some modifications. The medium was aspirated and the cells were harvested and lysed in 100 μl of denaturing buffer (1% SDS, 50 mM Tris pH7.4, 140 mM NaCl). Following vigorous vortexing, the lysates were immediately boiled for 10 minutes, cleared by centrifugation at 10,000 g for 10 minutes and diluted 10 fold into buffer containing 2% Triton X-100, 50 mM Tris pH7.4, 140 mM NaCl. After additional centrifugation to remove any insoluble material, immunoprecipitation was carried out with monoclonal anti-GCase antibody. Following three washes (5% sucrose, Tris pH7.5, 50 mM NaCl, 0.5% NP40, EDTA 5 mM) the ubiquitin-GCase conjugates were resolved through SDS-PAGE and the corresponding blots were interacted with polyclonal anti-GCase antibodies.
Cells were treated for 24 hours with 25 μM MG132, after which they were processed according to the experiment performed (western blotting with or without immunoprecipitation).
The blots were scanned using Image Scan and the intensity of each band was measured by the Image Master 1DPrime densitometer (both from Amersham Pharmacia Biotech, Buckinghamshire, England). To quantify the results, the intensity of the tested protein at each lane was divided by the intensity of the loading control (actin or ERK) in the same lane. The value obtained for non-transfected cells or WT cells was considered as 1.
Endogenous mutant GCase undergoes polyubiquitination and interacts with parkin
Parkin interacts with mutant GCase in GD fibroblasts
We have shown in the past that parkin and mutant GCase, expressed in heterologous systems, interact with each other. Moreover, parkin mediates polyubiquitination and proteasomal degradation of mutant, but not normal transfected GCase . In the present study, we aimed at confirming the interaction between endogenous parkin and mutant GCase. In order to do so, we first set out to demonstrate the expression of parkin in skin fibroblasts (Figure 1C). At the next stage, parkin-containing complexes were immunoprecipitated from lysates prepared from GD skin fibroblasts and from normal skin fibroblasts, after which the corresponding blot was interacted with anti-GCase antibody. The results presented in Figure 1D and E show that mutant GCase, but not its normal counterpart, interacted with parkin.
Parkin mediates degradation of endogenous mutant GCase
Competition between PARIS and mutant GCase
As shown thus far, parkin interacts with mutant GCase and mediates its degradation. We showed in a previous study that parkin, expressed in HEK293 cells, mediates K48 polyubiquitination and proteasomal degradation of mutant, but not normal, transfected GCase . Since PD is characterized by death of dopaminergic neurons in the substantia nigra pars compacta region of the brain, and accumulation of pro-apoptotic parkin substrates have been documented, we wondered whether a competition exists between known pathogenic parkin substrates and mutant GCase.
To summarize, our results imply that mutant GCase and PARIS compete on the availability of parkin. Thus, presence of mutant GCase leads to accumulation of cytoplasmic PARIS and down-regulation of genes associated with mitochondrial biogenesis, which may lead to cell death.
Competition between ARTS and mutant GCase
Mutant GCase enhances cleavage of caspase 3 and caspase 9, leading to apoptosis
Our results strongly indicate that mutant GCase leads to sensitization of cells to apoptotic stimuli and death, involving caspase cleavage.
In the present study we show that endogenous mutant GCase variants undergo polyubiquitination. They associate with parkin, which mediates their degradation, as shown by overexpression of normal or mutant parkin in GD-derived skin fibroblasts or by transfection of parkin shRNA into GD-derived fibroblasts. Mutant GCase variants compete with the pathogenic parkin substrates PARIS and ARTS. Based on the presented results, we hypothesize that the presence of mutant GCase in dopaminergic cells of GD patients or carriers of GD mutations leads to accumulation of pathogenic parkin substrates, which contributes to their death and to the development of PD.
Mutations in parkin, a RING domain-containing E3 ligase, are the most common cause of autosomal recessive PD [26, 45]. Parkin plays a role in the ERAD of misfolded ER proteins, and it is upregulated by unfolded protein stress . It induces proteasome-mediated mitophagy and degradation of mitofusins . Loss of parkin activity leads to the accumulation of its pathogenic substrates PARIS and AIMP2 (aminoacyl tRNA synthetase complex-interacting multifunctional protein-2) and to α-synuclein aggregation, ultimately causing cell death . PARIS is a transcription factor that undergoes parkin-mediated ubiquitination and proteasomal degradation in the cytoplasm. Its non-ubiquitinated form shuttles to the nucleus and represses the transcription of NRF1, whose target is ATPase5β. The latter encodes the beta subunit of complex V of the oxidative phosphorylation machinery in the mitochondria . AIMP2 is another substrate of parkin, present in Lewy body inclusions in the substantia nigra of PD patients [48, 49].
Parkin promotes clearance of depolarized mitochondria by mitophagy [50–52]. Mitophagy is the selective engulfment of mitochondria by autophagosomes and their subsequent degradation by lysosomes [53, 54]. Parkin is recruited to depolarized mitochondria where it mediates the ubiquitination of the mitochondrial outer membrane proteins mitofusin 1 and 2 [51, 55], thereby preventing the fusion of damaged mitochondria and targeting them for degradation by mitophagy [47, 51, 55, 56]. Interestingly, disease-associated parkin mutants were also shown to be defective in promoting mitophagy .
Another parkin substrate is Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. Endogenous Miro levels were significantly decreased in HEK293T cells overexpressing parkin, resulting in the release of kinesin from mitochondria and the detachment of mitochondria from microtubules .
Based on our results and the literature, we assume that occupation of parkin with mutant GCase affects its availability to bind other substrates, including PARIS, ARTS, mitofusins and Miro. This leads to decreased mitochondria biogenesis, prevents mitophagy and results in retention of damaged mitochondria, eventually leading to death of dopaminergic cells and to development of PD.
Phosphorylation of parkin by c-Abl and its interaction with 14-3-3eta were shown to inactivate its activity. Thus, the non-tyrosine receptor kinase c-Abl mediates dopaminergic stress or dopaminergic neurotoxin-induced tyrosine 143 phosphorylation of parkin. This modification leads to the inactivation of parkin, the subsequent accumulation of pathogenic parkin substrates, and to the eventual death of dopaminergic cells [59, 60]. Interaction of parkin with 14-3-3eta was shown to negatively regulate its activity. Alpha-synuclein abrogated the 14-3-3eta-induced suppression of parkin activity . However, PD-causing mutants of α-synuclein failed to activate parkin due to their inability to bind 14-3-3eta [59, 60].
Since carriers of GD mutations and Type 1 GD patients are prone to develop PD, and since the common denominator between these two populations is the existence of mutant GCase, we assume that the latter is a dominant predisposing factor for development of PD. It is of note that no GCase substrate (i.e. glucosylceramide) accumulation has ever been documented in brains of carriers of GD mutations or those of Type 1 GD patients. In a recent work we have shown that transgenic expression of mutant GCase in dopaminergic/serotonergic cells of the Drosophila melanogaster brain leads to development of PD-like symptoms, exemplified by the death of dopaminergic cells and motor impairment (climbing disability) .
Parkin is not the only E3 ubiquitin ligase involved in degradation of mutant GCase variants. Other E3 ubiquitin ligases such as c-Cbl  and Itch  have been recently reported to mediate the degradation of mutant GCase variants. It is not unusual that multiple E3 ligases contribute to the stability of substrates. Thus, at least five different E3 ligases have been already documented for p53 [63–67]. It is reasonable to assume that, under different conditions and in different cells, various E3 ligases regulate the levels of mutant GCase variants by modulating its polyubiquitination and proteasomal degradation.
To summarize, in the present work we show that mutant GCase variants undergo parkin-mediated degradation, a process that leads to the accumulation of pathogenic substrates such as PARIS and ARTS in cells. We assume that accumulation of such substrates in the dopaminergic cells of the brain is one of the factors that lead to their death and development of PD.
We thank Dr. Mirella Filocamo (Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, IRCCS G. Gaslini, Genova, Italy) and Dr. Roscoe Brady (NIH, Bethesda, MD, USA) for GD derived skin fibroblasts and Dr. Eli Sprecher (Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel) for normal fibroblasts. We thank Dr. Ted M. Dawson (Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA) for a kind gift of the PARIS expressing plasmid. We would like to express our appreciation to Dr. Doron Calo, Research Authority, Tel Aviv University, for critical reading of the manuscript. This work was supported by a grant from The Israeli Ministry of Health (MH). Inna Bendikov-Bar was the recipient of Gertner and SAIA fellowships, administered by Tel Aviv University.
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