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J. Biol. Chem., Vol. 283, Issue 12, 7554-7560, March 21, 2008

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Functional Mitochondria Are Required for -Synuclein Toxicity in Aging Yeast^*

Sabrina Büttner, Alessandro Bitto, Julia Ring, Manuela Augsten, Piotr Zabrocki¹, Tobias Eisenberg, Helmut Jungwirth, Sylvia Hutter, Didac Carmona-Gutierrez, Guido Kroemer^¶||**, Joris Winderickx²³, and Frank Madeo²⁴

From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria, Functional Biology, Catholic University of Leuven, B-3000 Leuven, Belgium, ^¶INSERM, U848, 94805 Villejuif, France, the ^||Institut Gustave Roussy, 94805 Villejuif, France, and the ^**University Paris-Sud, Paris 11, 94805 Villejuif, France

Received for publication, October 11, 2007 , and in revised form, December 31, 2007.

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 
-Synuclein is one of the principal toxic triggers of Parkinson disease, an age-associated neurodegeneration. Using old yeast as a model of -synuclein expression in post-mitotic cells, we show that -synuclein toxicity depends on chronological aging and results in apoptosis as well as necrosis. Neither disruption of key components of the unfolded protein response nor deletion of proapoptotic key players (including the yeast caspase YCA1, the apoptosis-inducing factor AIF1, or the serine protease OMI) did prevent -synuclein-induced cell killing. However, abrogation of mitochondrial DNA (rho⁰) inhibited -synuclein-induced reactive oxygen species formation and subsequent apoptotic cell death. Thus, introducing an aging yeast model of -synuclein toxicity, we demonstrate a strict requirement of functional mitochondria.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 
Parkinson disease (PD)⁵ is the second most frequent age-associated neurodegenerative disease. Several observations suggested malfunctioning of the protein -synuclein to be a toxic trigger of the neurodegenerative process during PD (1). Fibrillar -synuclein constitutes the major protein component of Lewy bodies in the brain of sporadic PD patients. Furthermore, three missense mutations (A53T, A30P, and E46K) in the -synuclein gene are linked to early onset dominant familial PD (2–4). Recently, overexpression of wild type -synuclein due to gene duplication or triplication was found to be sufficient to cause a familial form of PD (5). In mammalian cell culture, -synuclein has been reported to have polymorphic, dopamine-dependent neurotoxic effects as well as neuroprotective and antiapoptotic functions, depending on the specific type of neurons or mutants (6, 7). The biochemistry and pathogenicity of -synuclein has been studied extensively in non-human model organisms including flies, nematodes, and transgenic mice, suggesting a role for -synuclein in lipid and vesicle dynamics, proteasomal dysfunction, or oxidative stress (8–10). Still, the down-stream events or cell death executors required for -synuclein-mediated death remain elusive.

Most recently, the yeast Saccharomyces cerevisiae has been shown to succumb to human -synuclein expression. Using this new model, a conserved link between endoplasmic reticulum-Golgi traffic and -synuclein toxicity has been established (11, 12). In addition, yeast is increasingly recognized as a model organism for the study of apoptosis and necrosis (13, 14) as the basic molecular machinery executing cell death is phylogenetically conserved. Orthologues of caspases (Yca1p), the apoptosis-inducing factor (Aif1p), the serine protease OMI (Nma111p), and endonuclease G (Nuc1p) have been described (15–18). In addition, yeast apoptotic death occurs in dependence of complex apoptotic scenarios such as mitochondrial fragmentation (19), cytochrome c release (20), cytoskeletal pertubations (21), and histone H2B phosphorylation (22). Finally, chronologically aged yeast cells are currently used as a valuable model to study oxidative damage and molecular conserved aging pathways of post-mitotic mammalian cells, and recent studies have demonstrated that aged yeast cells die exhibiting an apoptotic phenotype (23–25). Here, we introduce chronologically aged yeast cultures as a new model to study -synuclein toxicity during aging. Using strains devoid of mitochondrial DNA (rho⁰), we demonstrate that mitochondrial function is required for the deleterious consequences of -synuclein expression.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 
Yeast Strains and Plasmids—Experiments were carried out in BY4741 (MATa his31 leu20 met150 ura30) and respective null mutants, obtained from Euroscarf. All strains were grown on SC medium containing 0.17% yeast nitrogen base (BD Diagnostics), 0.5% (NH₄)₂SO₄, and 30 mg/liter of all amino acids (except 80 mg/liter histidine and 200 mg/liter leucine), 30 mg/liter adenine, and 320 mg/liter uracil with 2% glucose or 2% galactose for induction of expression of -synuclein-FLAG constructs. Induction of -synuclein expression in rho⁰ strains was achieved using SC medium containing 1.5% galactose and 0.5% glucose since BY4741 rho⁰ cells are unable to grow on pure galactose medium. To construct WT-Syn^FLAG and A53T^FLAG, inserts were amplified by PCR with primers 3'-ATC TAC TAG TAT GGA TGT ATT CAT GAA AGG ACT TTC-5' and 3'-ATC TAT CGA TGT GGC TTC AGG TTC GTA GTC TTG-5', using previously described YEp181-synuclein or YEp181-A53T as template (26), cut with SpeI and ClaI and ligated into pESC-His (Stratagene). Fluorescence microscopy to detect protein aggregation was performed using previously published pUG23-WT-Syn^EGFP and pUG23-A53T^EGFP constructs (26). For abrogation of the mtDNA (rho⁰), BY4741 wild type cells were grown in full medium containing 10 µg/ml ethidium bromide for 3 days. The resulting respiratory deficiency was confirmed by complete lack of growth on obligatory respiratory medium (glycerol).

View larger version (36K): [in this window] [in a new window]   FIGURE 1. Age-dependent -synuclein-mediated death is accompanied by phenotypic manifestations of apoptosis and necrosis. A, survival determined by clonogenicity of WT cells expressing human -synuclein (WT-Syn) or the point mutant A53T or harboring the corresponding empty vector during chronological aging on 2% galactose synthetic media. A representative aging experiment is shown, with data representing mean ± S.E. of four independent experiments performed at the same time. CFU, colony-forming unit. B, quantification (fluorescence reader) of ROS accumulation using DHE staining at days 1, 3, and 5 of the aging experiment shown in A. Data represent mean ± S.E. of four independent experiments. In each experiment, 5 · 106 cells were evaluated. **, p < 0.01, ***, p < 0.001. RFU, relative fluorescence units. C, quantification (FACS analysis) of DNA fragmentation using TUNEL staining and of phosphatidylserine externalization and loss of membrane integrity using annexin V/PI costaining at day 3 of the aging experiment shown in A. In every experiment, 30,000 cells were evaluated. DIC, differential interference contrast. D, fluorescence microscopy of DHE, TUNEL, and annexin V/PI staining of wild type cells expressing WT-Syn or A53T or harboring the empty vector at day 3 of aging.

Immunoblotting—Preparation of cell extracts and immunoblotting were performed as described (16). Blots were probed with murine monoclonal antibodies against FLAG-epitope (Sigma), murine monoclonal antibodies against glyceraldehyde-3-phosphate dehydrogenase (Sigma), and the respective peroxidase-conjugated affinity-purified secondary antibody (Sigma).

View larger version (47K): [in this window] [in a new window]   FIGURE 2. -synuclein toxicity is exacerbated by the point mutation A53T on low galactose medium. A, survival determined by clonogenicity of WT cells expressing WT-Syn, A53T, or harboring the corresponding empty vector at indicated time points during prolonged expression on 0.5% galactose synthetic medium (lower expression levels). A representative aging experiment is shown, with data representing mean ± S.E. of six independent experiments performed at the same time. *, p < 0.05, **, p < 0.01. CFU, colony-forming unit. B, quantification of ROS accumulation using DHE staining at indicated time points of the experiment shown in A. Data represent mean ± S.E. of six independent experiments. In each experiment, 5 · 106 cells were evaluated. **, p < 0.01, ***, p < 0.001. DHE pos., DHE-positive; RFU, relative fluorescence units. C, Western blot analysis of WT-Syn and A53T expression in WT cells grown on 2% or 0.5% galactose synthetic medium, respectively. The blot was probed with -FLAG or -glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibody and the corresponding secondary antibodies. ctrl, control. D, fluorescence microscopy of WT cells expressing WT-SynEGFP, A53TEGFP, or harboring the corresponding empty vector.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

We next investigated whether -synuclein-mediated death of aged yeast cells is of apoptotic nature. To quantify the generation of reactive oxygen species (ROS), the superoxide-driven conversion of non-fluorescent DHE into fluorescent ethidium was assessed in an automated assay. The prolonged expression of WT-Syn or A53T caused massive generation of ROS (Fig. 1, B and D). Moreover, the excessive death of cells expressing WT-Syn or A53T was accompanied by a major increase (3-fold) in apoptotic DNA fragmentation as detectable by TUNEL staining (Fig. 1, C and D). The simultaneous detection of phosphatidylserine externalization and loss of membrane integrity with fluorescein isothiocyanate-conjugated annexin V and PI, respectively, discriminates between early apoptosis (annexin V⁺), late apoptosis eventually leading to secondary necrosis (annexin V⁺/PI⁺), and primary necrosis (PI⁺). As shown in Fig. 1C, expression of WT-Syn or A53T stimulated the apoptotic externalization of phosphatidylserine and simultaneously led to an increase in cells only positive for PI indicative of necrosis (Fig. 1, C and D). Similar results were obtained using the wild type W303 transformed with constructs allowing expression of -synuclein from the constitutive TPI1 promoter (data not shown). We conclude that -synuclein triggers both apoptosis and necrosis during chronological aging of yeast.

View larger version (30K): [in this window] [in a new window]   FIGURE 3. -synuclein toxicity during aging is independent of Yca1p, Aif1p, and OMI (Nma111p). A–C, survival during chronological aging of WT cells and yca1 (A), aif1 (B), or nma111 (C) cells expressing WT-Syn. Representative aging experiments are shown, with data representing mean ± S.E. of four independent experiments performed at the same time. CFU, colony-forming unit; ctrl, control. D, quantification (fluorescence reader) of ROS accumulation using DHE staining at days 1, 3, and 5 of Syn expression in WT, yca1, aif1, and nma111 cells. Data represent mean ± S.E. of four independent experiments. In each experiment, 5 · 106 cells were evaluated. ***, p < 0.001. DHE pos., DHE-positive. RFU, relative fluorescence units. E, Western blot analysis of WT-Syn expression in WT, yca1, aif1, and nma111 cells. The blot was probed with -FLAG or -glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibody and the corresponding secondary antibodies.

-Synuclein-mediated Death of Aged Cells Does Not Depend on the Apoptotic Key Players Yca1p, Aif1p, or OMI (Nma111p)—Recent studies indicated that the mammalian apoptotic serinep-rotease OMI (also called HtrA2) and the yeast caspase Yca1p might be involved in -synuclein-mediated toxicity (27, 28). Therefore, we comparatively analyzed -synuclein-mediated cell killing during chronological aging in yeast cells lacking YCA1, NMA111, or the mitochondrial apoptosis-inducing factor AIF1. Deletion of YCA1 had no effect on cell survival upon WT-Syn expression during aging (Fig. 3A). Consistently, -synuclein-induced DHE-detectable ROS accumulation during chronological aging was not affected by the absence of YCA1 (Fig. 3D). These results were confirmed using another ROS-sensitive probe, dihydrorhodamine (data not shown). Cytofluorometric quantification of DNA fragmentation (TUNEL) and phosphatidylserine externalization and/or membrane permeabilization (annexin V/PI costaining) further confirmed that Yca1p did not influence the -synuclein-facilitated cell killing (data not shown). Furthermore, neither deletion of AIF1 nor deletion of NMA111 reduced -synuclein-mediated death (Fig. 3, B and C) or ROS production during chronological aging (Fig. 3D). Similar expression levels of -synuclein were confirmed in all knock-out strains using Western blot analysis (Fig. 3E).

View larger version (44K): [in this window] [in a new window]   FIGURE 4. -synuclein-mediated death of aged yeast cells depends on mitochondrial function. A and B, survival determined by clonogenicity during chronological aging of WT (A) and rho0 (B) cells expressing WT-Syn or A53T on 1.5% galactose, 0.5% glucose synthetic medium. A representative aging experiment is shown, with data representing mean ± S.E. of four independent experiments performed at the same time. CFU, colony-forming unit. C, survival of WT and rho0 cells expressing WT-Syn or A53T at indicated time points during prolonged expression. Data represent mean ± S.E. of four independent experiments. D, quantification of ROS accumulation using DHE staining at the indicated time points of the experiment shown in C. Data represent mean ± S.E. of four independent experiments performed at the same time. In each experiment, 30,000 cells were evaluated using FACS analysis. E, quantification of phosphatidylserine externalization and loss of membrane integrity using annexin V/PI costaining at the indicated time points of the experiment shown in C. In each experiment, 30,000 cells were evaluated using FACS analysis. ctrl, control.

Functional Mitochondria Are Essential for -Synuclein Toxicity—Oxidative processes mediated by enhanced ROS production are prominent traits of apoptosis and organismal aging throughout phylogeny. ROS are generated mainly from two sources: the mitochondrial respiratory chain and the unfolded protein response (UPR) machinery. The accumulation of misfolded proteins within the endoplasmic reticulum leads to prolonged activation of the UPR, which in turn causes oxidative stress and finally cell death in yeast (30). To test whether -synuclein-mediated death depends on the UPR-activated cell death pathway, -synuclein was expressed in the deletion mutants ire1 and hac1, two key players of the UPR. Ire1p initiates the UPR by regulating the synthesis of the transcription factor Hac1p (31). Neither deletion of IRE1 nor deletion of HAC1 affected -synuclein-mediated toxicity (supplemental Fig. S1), suggesting a pathway in which UPR signaling via Ire1p and Hac1p does not contribute to the loss of viability induced by -synuclein. As mammalian and yeast apoptosis are under mitochondrial control (17, 19, 20, 32, 33), we next investigated the impact of mitochondrial function on -synuclein-triggered cell death. Therefore, we generated cells that lack mitochondrial DNA (rho⁰) and thus are incapable of oxidative phosphorylation. Contrasting with its marked toxicity on wild type (rho⁺) cells, enforced expression of WT-Syn or A53T failed to provoke the death of rho⁰ cultures during chronological aging (Fig. 4, A and B), although rho⁰ and wild type cells expressed similar levels of -synuclein (data not shown). It should be noted that the lack of respiratory function via abrogation of mtDNA compromised overall survival during aging, presumably because these cells cannot switch from fermentation to respiration during the diauxic shift. Thus, we decided to closely monitor the kinetics of early -synuclein-mediated death in wild type and rho⁰ cells. Wt-Syn and A53T expression led to massive cell killing in the wild type at early time points (16–48 h) of aging, whereas death was completely inhibited in rho⁰ cells (Fig. 4C). Concomitantly, the deletion of mtDNA completely inhibited -synuclein-induced ROS-generation (as determined by DHE staining, Fig. 4D) and phosphatidylserine externalization (Fig. 4E). Remarkably, at early time points of aging, death caused by WT-Syn or A53T expression is predominantly due to apoptosis since cells only positive for PI did not increase within the first 48 h (Fig. 4E). Thus, abrogation of mtDNA, and therefore respiratory function, suppresses the apoptotic component of -synuclein-mediated yeast cell killing.

Interestingly, upon deletion of the mtDNA, and therefore prevention of the toxic function of -synuclein, expression of WT-Syn but not of A53T even suppressed the onset of apoptotic markers. At early time points, WT-Syn expressed in rho⁰ cells significantly reduced the accumulation of ROS when compared with the corresponding vector control (p = 0.024 at 24 h) (Fig. 4D). Additionally, the externalization of phosphatidylserine and the loss of membrane integrity was diminished upon expression of WT-Syn but not of A53T (Fig. 4E). These data are consistent with previous findings in mammalian cells showing that -synuclein can have antiapoptotic functions (6, 7). In yeast, this protective effect becomes apparent only after abrogation of the toxic function via deletion of mtDNA and is absent in the A53T point mutant.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 
In this study, we investigated -synuclein-mediated toxicity during chronological aging of yeast cells using clonogenic assays combined with the assessment of cell death markers. Our data indicate that expression of WT-Syn and the early onset PD-associated point mutant A53T dramatically reduces the survival of aging yeast cells due to a marked increase in ROS generation and the induction of apoptotic and necrotic cell death. These data extend previous observations made in yeast showing that -synuclein-induced toxicity is related to the ability of -synuclein to interact with the plasma membrane and to form inclusions (12, 26). In contrast to earlier findings using exponentially growing yeast cells expressing -synuclein (27), our results indicate that -synuclein toxicity does not depend on the metacaspase Yca1p. Recent observations in mammalian cellular models and histopathological specimens from PD patients indicate enhanced UPR activity to be a primary cause for the loss of viability (34) and the apoptotic serine protease Omi/HtrA2 to be an executor of -synuclein-mediated cell death (28). However, in yeast, neither key components of the UPR nor Omi (Nma111p) or the apoptosis-inducing factor Aif1p seem to impart -synuclein toxicity. Deregulation of the N-methyl-D-aspartic acid subtype glutamate receptor, malfunctioning of the ATP-sensitive potassium channels (35), or dopamine metabolites leading to oxidative damage (36) have been suggested to account for selective dopaminergic degeneration in PD. However, in yeast, -synuclein must rely on other, more general mechanisms, for the simple reason that yeast lacks analogues of neuron-specific ion channels or neurotransmitters.

Oxidative stress and mitochondrial dysfunction have long been recognized as key factors that operate in the pathogenesis of PD (9). A significant reduction of cardiolipin in mitochondrial membranes concomitant with a drop in complex II and complex III activity was noticed in -synuclein knock-out mice (37). The recent discovery of the mitochondria-associated proteins Parkin, DJ-1, and PINK1 has further strengthened the importance of mitochondrial functions and placed apoptosis to the forefront of PD biology (38, 39). In this line, our studies identified mitochondrial function and oxidative phosphorylation as central players in -synuclein-mediated apoptosis and necrosis of yeast cells since deletion of mtDNA completely abrogates the toxic function of WT-Syn and A53T. It should be noted that survival of rho⁰ cells is compromised during aging, especially at later time points (since these cells cannot switch from fermentation to respiration during the diauxic shift). Nonetheless, under conditions where deletion of mtDNA itself does not sensitize cells to apoptosis (early time points during aging, Fig. 4, C and D), it still clearly protects cells against death mediated by -synuclein expression. Moreover, under these conditions, a protective function of WT-Syn on apoptotic and necrotic markers is observable. Once more, these studies show the potential offered by yeast models for defining novel fundamental mechanisms and factors involved in the pathogenesis of PD.

	FOOTNOTES

 
^* This work was supported in part by grants from the Fonds zur Förderung der wissenschaftlichen Forschung (Austria) (Grant S-9304-B05) (to F. M., S. B., and D. C.-G.), Deutsche Forschungsgemeinschaft (Germany) (Grant MA2587) (to F. M. and T. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ Supported by a European Community Marie Curie fellowship (MEIF-CT-2005-514281) and supported by the Marie Curie Ph.D. Graduate School Neurodegeneration in Alzheimer's Disease (NEURAD).

² Both authors share equally contributing senior authorship.

³ Supported by the Fund for Scientific Research-Flanders (Fonds Weten-schappelijk Onderzoek-Vlaanderen), the KULeuven Research Fund (KULeuven-BOF), and the KULeuven R&D. To whom correspondence may be addressed: K.U. Leuven, Kasteelpark Arenberg 31, B-3001 Heverlee, Belgium. Fax: 32-16-321967; E-mail: joris.winderickx{at}bio.kuleuven.be. ⁴To whom correspondence may be addressed: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria. Fax: 43-316-3809898; E-mail: frank.madeo{at}uni-graz.at.

⁵ The abbreviations used are: PD, Parkinson disease; ROS, reactive oxygen species; DHE, dihydroethidium; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling; PI, propidium iodide; UPR, unfolded protein response; FACS, fluorescence-activated cell sorter; WT-Syn, wild type -synuclein.

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TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 

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