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Research Article

Differential regulation of caspase-2 in MPPþ-induced apoptosis in primary cortical neurons Hsin-I Hua, Hsin-Hou Changa,b, Der-Shan Suna,b,n a

Department of Molecular Biology and Human Genetics, Tzu-Chi University, No. 701, Section 3, Zhong-Yang Road, 97004 Hualien, Taiwan, ROC b Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan, ROC

article information

abstract

Article Chronology:

Parkinson's disease (PD), among the most common neurodegenerative diseases worldwide for which

Received 1 September 2014

there is no cure, is characterized as progressive dopaminergic neuron loss in the substantia nigra

Received in revised form

through an unknown mechanism. Administering 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

15 December 2014

(MPTP) causes neuronal cell death and Parkinsonism in humans. Commonly used in animal models of

Accepted 21 January 2015

PD, MPTP can metabolize to 1-methyl-4-phenylpyridinium (MPPþ); however, the detailed mechan-

Available online 30 January 2015

ism through which MPPþ causes neuronal cell death remains undetermined. Previous reports

Keywords: Parkinson's disease þ

MPP

Apoptosis Primary cortical neurons Caspase-2 Mitochondria

have indicated those knockout mice with Bcl-2 associated protein X (Bax) or caspase-2, two mitochondrial outer membrane permeabilization inducers, are resistant to MPTP administration, suggesting that mitochondria are involved in MPPþ-triggered apoptosis. Our previous study showed that MPPþ-triggered apoptosis can be distinguished from spontaneous apoptosis of primary cortical neurons. In the present study, we verified the involvement of mitochondria in MPPþ-induced and spontaneous apoptosis in cortical neurons through confocal microscope analysis. We demonstrated that caspase-2 activation is specific to MPPþ-induced apoptosis and occurs before Bax translocation to the mitochondria. Caspase-2 activation is one of the few early molecular events identified in PD models. & 2015 Elsevier Inc. All rights reserved.

Introduction Parkinson's disease (PD) is among the most common neurodegenerative disorders, affecting more than 6 million people

worldwide [1]; however, no cure has been discovered. PD is classified as a motor neuron defect caused by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and other monoaminergic neurons in the cerebral cortex [2,3]; the

Abbreviations: PD, Parkinson's disease; MPTP, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine; MPPþ, 1-methyl-4-phenylpyridinium; MOMP, mitochondrial outer membrane permeabilization; PCD, programmed cell death pathway; Bax, Bcl-2 associated protein X; JNK, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase; DAPI, 40 -6-diamidino-2-phenylindole; Smac, second mitochondriaderived activator of caspase; AIF, apoptosis inducing factor n Corresponding author at: Department of Molecular Biology and Human Genetics, Tzu-Chi University, No. 701, Section 3, Zhong-Yang Road, 97004 Hualien, Taiwan, ROC. Fax: þ886 3 8561422. E-mail address: [email protected] (D.-S. Sun).

http://dx.doi.org/10.1016/j.yexcr.2015.01.011 0014-4827/& 2015 Elsevier Inc. All rights reserved.

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progressive loss of neurons are involved in cell death caused by apoptosis, autophagic cell death, or programmed necrosis [4,5]. The major symptoms of PD are resting tremor, slowness of voluntary movement, rigidity, and postural instability [6]. Knowledge of how the neurodegenerative process occurs in dopaminergic neurons has been derived primarily from neurotoxininduced animal models of PD [6,7]. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), one of the most extensively characterized and widely used toxin in animal models of PD, is a byproduct of meperidine analog synthesis and exerts potent heroin-like effects that can induce Parkinsonism in humans. After administration, MPTP can penetrate the blood–brain barrier and be metabolized to 1-methyl-4phenylpyridinium (MPPþ) by monoamine oxidase B in glial cells. Once MPPþ is transmitted to neurons by dopaminergic transporters, it impairs mitochondria complex I, subsequently increases free radicals, and finally induces oxidative stress in the mitochondria, initiating a programmed cell death (PCD) pathway [8]. However, the mechanism through which PCD occurs after MPPþ impairs mitochondria complex I remain unclear [9]. PCD, also known as apoptosis, is characterized by membrane blebbing, shrinkage of the cell body, nuclear condensation, and DNA fragmentation. Induction of Bcl-2 associated protein X (Bax) and mitochondrial outer membrane permeabilization (MOMP) has been suggested to result in cytochrome c release into the cytosol of the ventral midbrain in an MPTP mouse model [10,11]; this suggestion is consistent with the observation that Bax knockout mice were more resistant to MPTP neurotoxicity than were wild type mice [11]. Caspases are a family of cysteine-specific protease associated with the initiator or effector of apoptosis [12]. Caspase2 induces MOMP through cleavage and activation of Bid [13]. Capase-2 knockout mice exhibited greater resistance to MPTPinduced neurotoxicity than did wild type mice [14]. In addition, previous studies have reported that caspase-2 was involved in MPPþ-induced cell death in primary cultures of mesencephalic dopaminergic neurons and the MN9D mouse dopaminergic cell line [15,16]. This evidence indicates that the mitochondriamediated apoptosis pathway is involved in MPTP-induced neurotoxicity. Caspase-2 is one of the less extensively characterized members in the caspase family; its role in PD and its relationship with Bax in MPPþ-induced neuronal cell death require further investigation. Currently, there are no effective treatments for PD. Administering a dopamine agonist (L-dopa) combined with other enzyme inhibitors, such as the MAO-B inhibitor and peripheral decarboxylase inhibitors, to patients with PD is a symptomatic approach for ameliorating the motor deficits associated with PD [6]. Furthermore, long-term treatment with L-dopa was reported to lead to dyskinesia in patients with young-onset PD [17]. Because there is no effective treatment, a treatment that reduces neuronal degeneration is urgently required. Our research team established a primary cortical neuron culture system to investigate the molecular mechanism of MPPþ-induced neuronal cell death [18]. In this culture system, we observed that two types of caspase-3-mediated apoptosis contributed to total cell death: MPPþ-triggered apoptosis and basal-level apoptosis, which spontaneously occurs in MPPþ-untreated long-term culture cells. The regulation of stress-activated protein kinase (SAPK)/c-Jun Nterminal kinase (JNK) activity in these two apoptotic responses

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differs [18]. In the present study, we characterized the molecular mechanism of mitochondria-mediated apoptosis in these two apoptotic responses.

Materials and methods Animals ICR mice were obtained from the National Laboratory Animal Center (Taipei, Taiwan) and maintained in the Animal Experimentation Center of Tzu-Chi University. Two female mice were placed with one male mouse at 5:00 p.m., and the female mice were separated from the male mice the next morning. The pregnant mice were examined using vaginal plugs and sacrificed 13.5 days after gestation. All procedures involving animal manipulation were conducted according to the national guidelines of the Animal Protection Act (Taiwan) and approved by the Institutional Animal Care and Use Committee of Tzu-Chi University.

Primary cortical neuronal cell cultures Cortical neurons were isolated from ICR mice embryos 13.5 days after gestation as described previously [18]. Neuronal cells were seeded on 96-well dishes (6  104 cells/well) for a viability assay, on 24-well dishes (1.5  105 cells/well) for an immunocytochemistry assay, and on 100 mm culture dishes (6.5  106 cells/well) for protein extraction. Culture dishes 100 mm in diameter were precoated with polyethylenimine (1 mg/mL, Sigma) overnight at 37 1C. Neuronal cells placed in 24-well and 96-well culture dishes were seeded on a 5  5-mm2 piece of glass, which was precoated with poly-D-lysine (50 μg/mL, Sigma) for 30 min at 37 1C. Cells were cultured in Dulbecco's Modified Eagle's Medium for 4 h before attachment. Neurobasal (Gibco BRL) supplemented with 2% B27 (Gibco BRL) and 10% fetal calf serum (Biological Industries) was used to culture primary cortical neurons.

Cell viability The cortical neurons were cultured on 96-well dishes for 6 days (days in vitro, DIV 6) and then treated with 20 μM MPPþ for various time periods (6, 18, 24, 36, or 48 h). Untreated cortical neurons cultured for the same time periods were used as controls. For a caspase-2 inhibition assay, the DIV 6 cortical neurons were treated with 50 μM z-VDVAD-fmk (Calbiochem) for 1 h at 37 1C, and some of the neurons were then treated with 20 μM MPPþ for various time periods (6, 24, or 48 h). Untreated caspase-2 inhibitor neurons at the same time points were used as controls. After the cell were washed with phosphate-buffered saline (PBS) once, the level of viable cells was observed and photographed using an inverted microscope (Axiovert 40 CFL, Carl Zeiss, Gottingen, Germany) and analyzed using the WST-1 (4-[3- (4iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1, 3-benzene disulfonate) kit according to the manufacturer's instructions (Roche Diagnostics). WST-1, a tetraxolium salt (slightly red), can be cleaved to formazan (dark red) by mitochondrial dehydrogenases. The absorbance of the formazan at 440 nm is correlated with the number of viable cells.

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Immunofluorescence and confocal microscopy The cortical neurons were cultured on 24-well dishes for 6 days (DIV 6) and then treated with 20 μM MPPþ for various time periods (6, 18, 24, 36, or 48 h). Untreated neurons at the same time points were used as controls. To determine the locations of mitochondria, cells were incubated with 50 μL of 2 μM Mitotracker Red CMXRos (Molecular Probes) for 30 min at 37 1C. After the cells were washed with PBS three times, they were fixed and permeablized with 4% paraformaldehyde and 0.1% Triton X-100 in PBS for 30 min at 37 1C. Fixed cells were treated with 5% bovine serum albumin for 1 h at room temperature and incubated with antibodies against Bax (BD Pharmingen), cytochrome c (BD Pharmingen), and Smac/DIABLO (BD Biosciences) overnight at 4 1C. After incubation, the cells were washed with PBS three times and incubated with secondary antibodies conjugated with fluorescein isothiocyanate (FITC) for 1 h at 37 1C. Cell nuclei were detected using 2 ng/mL of 40 -6diamidino-2-phenylindole (DAPI) fluorescent dye for 5 min at room temperature. Finally, the cells were mounted with antifade mounting solution (20 mM N-propyl-gallate, 50% glycerol in PBS) and examined through confocal laser microscopy (Leica TSC SP2).

Western blot Western blot analysis was performed according to a previously described method [18]. Briefly, 30 μg of protein extracts from neuronal cells that were or were not treated with 20 μM MPPþ for 6 or 48 h were separated through electrophoresis on 10% SDSpolyacrylamide gels (SDS-PAGE). After the proteins were transferred to nitrocellulose papers, the membranes were incubated with 1000-fold diluted anti-caspase-2 antibody (BD Pharmingen) overnight at 4 1C. After the nitrocellulose paper was washed with PBS three times, secondary antibodies conjugated with horseradish peroxidase were added for 1.5 h at room temperature. Immunoreactive signals were visualized by SuperSignal West Pico Chemiluminescent Substrate (Pierce Chemical). To normalize protein loading and transfer efficiency, the membranes were incubated with a β-tubulin antibody (BD Pharmingen).

Statistical analysis Statistical results are presented as means7standard deviation (SD). The significance of data was analyzed using a one-way ANOVA followed by a post-hoc Bonferroni-corrected t test. A p value o0.05 was considered significant.

Results Spontaneous cell death was slower than MPPþ-triggered cell death in primary cortical neurons To understand the progress of neuronal cell death, DIV 6 cortical neurons were or were not treated with 20 μM MPPþ for 6, 18, 24, 36, or 48 h. Cell morphology analysis indicated that fragmented dendrites and bubbled and shrinking cell bodies appeared more in the MPPþ-treated groups than in the MPPþ-untreated cultures at the same time points (Fig. 1A). Quantitative data indicated that MPPþ triggered swifter cell death progression, affected approximately 40% of the cells in only 6 h. By contrast, the same level of

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spontaneous cell death in MPPþ-untreated cells required 24 h (Fig. 1B). Within 48 h after the treatments, MPPþ caused highlevel cell death (95%). By contrast, 30% of the cells in the untreated groups remained alive (Fig. 1B). The data indicated that MPPþ-induced neuronal cell death occurred more rapidly than did death in the untreated control groups.

Dynamic changes in the cellular localization of mitochondria-related molecules (Bax, Smac, and cytochrome c) differed in spontaneous and MPPþ-induced neuronal cell death To assess the changes in cellular localization of mitochondriarelated molecules, DIV 3 primary cortical neurons and DIV 6 primary cortical neurons treated with MPPþ for 6 or 24 h were subjected to immunocytochemical analysis. Our data indicated that Bax was not translocated to the mitochondria, whereas two other mitochondria intermembrane proteins, namely the second mitochondria-derived activator of caspase (Smac) and cytochrome c, remained on the mitochondria on the DIV 3 primary cortical neurons (Fig. 2). Bax was partially translocated to the mitochondria after MPPþ treatment for 6 h, and the translocation was nearly complete after treatment for 24 h (Fig. 2A). By contrast, Smac and cytochrome c remained on the mitochondria at the same time points (Fig. 2B and C). The data indicated that mitochondria-dependent apoptosis was initiated 6 h after MPPþ treatment. Bax translocation to the mitochondria occurred before Smac and cytochrome c translocation from the mitochondria to the cytoplasm. Bax was translocated to the mitochondria in DIV 6 primary cortical neurons that were or were not treated with MPPþ for 48 h (Fig. 3A). Consistent with our findings that cell death occurred sooner in neurons treated with MPPþ than in those subjected only to longterm culture, Smac and cytochrome c were translocated from the mitochondria to the cytoplasm in DIV 6 primary cortical neurons after MPPþ treatment for 48 h (Fig. 3B and C). By contrast, at this time point, Smac was only partially translocated to the cytoplasm and cytochrome c remained on the mitochondria in neurons subjected to long-term culture (Fig. 3B and C). Our data indicated that the mitochondria-dependent apoptosis pathway was involved in two cell death responses.

Caspase-2 contributes to MPPþ-induced neuronal cell death To investigate whether caspase-2 is involved in the MPPþ-induced cell death of primary cortical neurons, the caspase-2 specific inhibitor Z-VDVAD-fmk was used in a cell viability assay. Our data revealed that the caspase-2 inhibitor ameliorated MPPþ-induced cell death, but not spontaneous apoptosis (Fig. 4). To verify the involvement of caspase-2 in MPPþ-induced cell death, Western blot analysis was performed. Caspase-2-cleaved fragments (14 kDa) were only observed in MPPþ-treated samples (Fig. 5, lanes 2 and 4), but not in MPPþ-untreated samples at the same time points (Fig. 5, lanes 1 and 3). This indicated that caspase-2 activity is specific to MPPþ-induced neuronal cell death.

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Fig. 1 – Cell viability of primary cortical neurons that were or were not treated with 20 μM MPPþ. DIV 6 primary cortical neurons cells were untreated (left) or treated (right) with 20 μM MPPþ for 6, 24, or 48 h. (A) Cells were observed and photographed using an inverted microscope (scale bar: 240 μm). (B) Cell viability was quantified by conducting a WST-1 assay. The cell viability of untreated cells for 6 h was defined as 100%. Data are presented as the mean7SD from three independent experiments; *po0.05, **po0.01.

Discussion Our previous study showed that MPPþ-induced and spontaneous cortical neuronal cell death both depended on activation of caspase-3, whereas differential regulation of JNK was involved in apoptotic cell death [18]. In this study, our data revealed that both MPPþ-induced and spontaneous cortical neuronal cell death involved a mitochondria-dependent apoptosis pathway, in which MPPþ induced a

swifter response. We also observed that caspase-2 activity was involved in MPPþ-induced neuronal cell death, which occurred before the mitochondria-dependent apoptotic response. Among various species of caspase, caspase-2 is the most conserved [19,20]; however, whether the major role of caspase-2 is apoptosis remains undetermined. Previous studies have proposed that DNA repair, cell cycle regulation, tumor suppression, autophagy, and cell survival are related to caspase-2 activity [19,21–23]. Our previous study showed that caspase-3 was eventually activated in

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Fig. 3 – Comparison of the cellular localization of Bax, Smac, and cytochrome c in DIV 6 primary cortical neurons in the presence or absence of MPPþ for 48 h. Cells were incubated with antibodies against (A) Bax, (B) Smac, and (C) cytochrome c and visualized through confocal microscopy. DAPI and Mitotracker Red CMXRos (Mit) were used to localize the nuclei and mitochondria, respectively (scale bar: 20 μm).

Fig. 2 – Dynamic changes in the cellular localization of Bax, Smac, and cytochrome c of DIV 3 primary cortical neurons and DIV 6 primary cortical neurons after MPPþ treatment for 6 or 24 h. Cells were incubated with antibodies against (A) Bax, (B) Smac, and (C) cytochrome c followed by FITC-conjugated secondary antibodies. Cells were visualized through confocal microscopy. DAPI and Mitotracker Red CMXRos (Mit) were used to localize the nuclei and mitochondria, respectively (scale bar: 20 μm). primary cortical neurons with or without MPPþ treatments [18]. The present study demonstrated that a caspase-2 inhibitor ameliorated MPPþ-induced cell death, but not spontaneous cortical neuronal cell death (Fig. 4), suggesting that caspase-2 activation is involved in MPPþ-induced neuronal cell death. Thus, our cortical neuron model includes two cell death pathways: spontaneous cell death involved

Fig. 4 – Effect of a caspase-2 inhibitor on the cell viability of DIV 6 primary cortical neurons untreated or treated with MPPþ for 6, 24, or 48 h. DIV 6 cortical neurons were untreated or treated with 50 μM caspase-2 inhibitor-Z-VDVAD-fmk for 1 h at 37 1C, and then some of the neurons were treated with 20 μM MPPþ for 6, 24, or 48 h. Cell viability was quantified using the WST-1 kit. The cell viability of DIV 6 untreated cells after 6 h was defined as 100%. Data are presented as the mean7SD from three independent experiments; po0.01 in a comparison between indicated groups.

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Fig. 5 – Monitoring the activation of caspase-2 by using Western blotting. DIV 6 cortical neurons were incubated in the absence (lanes 1 and 3) or presence (lanes 2 and 4) of 20 μM MPPþ for 6 h (lanes 1 and 2) and 48 h (lanes 3 and 4). Protein extracts (30 μg) were separated by 10% SDS-PAGE and immunoblotted with anti-caspase-2 antibody. β-tubulin was used as an internal loading control.

in caspase-3 activation and MPPþ-induced cell death involved in both caspase-3 and casepase-2 activation. Bax translocation to the mitochondrial outer membrane is the most vital step in initiating MOMP; however, the regulation of this process remains unclear [11,14,24]. Previous studies have reported that caspase-2 and Bax knockout mice are more resistant to MPTP-induced toxicity than are wild type mice [11,14], implying that both caspase-2 and Bax are involved in MPTP- or MPPþ-induced neuronal cell apoptosis. However, the relationship between caspase-2 and Bax in MPPþ-induced neuronal cell apoptosis remains unclear. Our data indicated that caspase-2 was activated on DIV 6 after MPPþ treatment for only 6 h (Fig. 5); however, at the same time point, Bax was only partially translocated to the mitochondria (Fig. 2A). These results indicated that caspase-2 functions as an initiator caspase, acting before the mitochondria in MPPþ-induced apoptosis in primary cortical neurons. This phenomenon is similar to apoptosis induced by the mitochondria complex I inhibitor rotenone in primary adult cortical neurons [25] and by the 6-hydroxydopamine in MN9D dopaminergic neuronal cells [26]. Caspase-2 has been reported to cleave Bid to form tBid [13,27], which was then integrated into the outer membranes of mitochondria to incorporate Bax, thereby forming pores [28]. Whether tBid is involved in MPPþ-induced apoptosis in primary cortical neurons requires further investigation. After Bax assembles into pores on the mitochondrial outer membrane, numerous proapoptotic proteins, including cytochrome c, apoptosis-inducing factor (AIF), endonuclease G, and Smac, are released from the mitochondrial intermembrane space to the cytosol. Cytochrome c binds to Apaf-1 and dATP to form an active apoptosome complex, which activates caspase 9 and triggers the downstream caspase cascade [29–31]. Smac binds to inhibitor of apoptosis proteins to sequester the inhibition on caspase-9, and then contributes to activating the caspase-9 apoptosis pathway [32]. However, whether all proapoptotic proteins are released from the mitochondria simultaneously is unclear. For example, cytochrome c was released from mitochondria earlier than AIF, endonuclease G, and Smac in neuronal cells in some studies [33,34], but cytochrome

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c and Smac were released together before AIF and endonuclease G in another study [35]. Although both MPPþ-elicited and spontaneously elicited neuronal cell death involved caspase-3-mediated apoptosis [18], MPPþ-induced apoptosis occurred considerably faster than did spontaneous apoptosis (Fig. 1). In our study, Smac and cytochrome c were translocated to the cytosol completely after MPPþ treatment for 48 h; however, cytochrome c remained on the mitochondria, and Smac was partially released to the cytosol at the same time point in the cells subjected to only long-term culture (Fig. 3B and C). This result implied that Smac is released before cytochrome c during spontaneous apoptosis in cortical neurons. JNK activity has been demonstrated to activate caspase-2 in docetaxel- and amyloid-β-peptide-induced apoptosis [36,37]. Our data indicated that caspase-2 activity is specific to MPPþ-induced apoptosis (Fig. 5) and can facilitate developing a therapeutic strategy that involves using caspase-2 inhibitors for cell-death intervention (Fig. 4). Our previous study indicated that JNK is downregulated in MPPþ-treated cortical neuronal cells [18]. These results suggest that JNK activation is probably not involved in the activity of caspase-2 during MPPþ-induced apoptosis. In addition, our data indicated that two cleaved forms of caspase-2 (37 and 19 kDa) appeared on untreated cells subjected to long-term culture; these two cleaved forms of caspase-2 did not affect cell survival. However, the role of these two cleaved forms of caspase-2 requires further investigation. In summary, this study demonstrated that caspase-2 activity is involved in MPPþ-induced apoptosis, which occurs before the mitochondria apoptosis pathway activation in primary cortical neuronal cells.

Conflict of interest The authors declare no confict of interest.

Acknowledgments This study was supported by Grants from the National Science Council (NSC 92-2321-B-320-002) and Tzu-Chi University (TCMRC 911002). We are grateful to Professor MH Wang and his team at the Animal Experimentation Center of Tzu-Chi University for their careful animal maintenance.

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Differential regulation of caspase-2 in MPP⁺-induced apoptosis in primary cortical neurons.

Parkinson's disease (PD), among the most common neurodegenerative diseases worldwide for which there is no cure, is characterized as progressive dopam...
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