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The Journal of Neuroscience, April 15, 2003, 23(8):3095
BRIEF COMMUNICATION
 -Synuclein Overexpression Protects against Paraquat-Induced
Neurodegeneration
Amy B.
Manning-Bo ,
Alison L.
McCormack,
Maya G.
Purisai,
Laurel M.
Bolin, and
Donato A.
Di
Monte
The Parkinson's Institute, Sunnyvale, California 94089
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ABSTRACT |
 -Synuclein is likely to play a role in neurodegenerative
processes, including the degeneration of nigrostriatal dopaminergic neurons that underlies Parkinson's disease. However, the toxicological properties of -synuclein remain relatively unknown. Here, the relationship between -synuclein expression and neuronal injury was
studied in mice exposed to the herbicide paraquat. Paraquat neurotoxicity was compared in control animals versus mice with transgenic expression of human -synuclein driven by the tyrosine hydroxylase (TH) promoter. In control mice, paraquat caused both the
formation of -synuclein-containing intraneuronal deposits and the
degeneration of nigrostriatal neurons, as demonstrated by silver
staining and a reduction of the counts of TH-positive and Nissl-stained
cells. Mice overexpressing -synuclein, either the human wild-type or
the Ala53Thr mutant form of the protein, displayed paraquat-induced
protein aggregates but were completely protected against
neurodegeneration. These resistant animals were also characterized by
increased levels of HSP70, a chaperone protein that has been shown to
counteract paraquat toxicity in other experimental models and could
therefore contribute to neuroprotection in -synuclein transgenic
mice. The results indicate a dissociation between toxicant-induced -synuclein deposition and neurodegeneration. They support a role of
-synuclein against toxic insults and suggest that its involvement in
human neurodegenerative processes may arise not only from a gain of
toxic function, as previously proposed, but also from a loss of
defensive properties.
Key words:
Parkinson; pesticide; inclusion; substantia nigra; HSP70; chaperone
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Introduction |
The tendency of -synuclein to
aggregate into nonfibrillar and fibrillar structures (Conway et al.,
1998 ; Giasson et al., 1999) is likely to explain, at least in part, its
involvement in the formation of intracellular inclusions typical of
diseases such as Parkinson's disease (PD), dementia with Lewy bodies,
and multiple system atrophy (Spillantini et al., 1998; Tu et al., 1998). Evidence also suggests that -synuclein may play a role in the
neurodegenerative processes that underlie these diseases (Polymeropoulos et al., 1997; Spira et al., 2001). However, the toxicological properties of -synuclein remain relatively unknown, and studies in various experimental models have failed to show a
consistent relationship between -synuclein expression and neuronal injury (Masliah et al., 2000; Ostrerova-Golts et al., 2000; Matsuoka et
al., 2001; Hashimoto et al., 2002). It has been hypothesized that
pathological changes may arise from interactions of -synuclein with
toxic agents, providing a mechanism by which environmental risk factors
could contribute to the pathogenesis of PD (Di Monte et al., 2002). In
support of this hypothesis, in vitro findings have revealed
that incubations of recombinant -synuclein in the presence of
pesticides, such as the herbicide paraquat, result in a dramatic
acceleration of protein fibrillation (Uversky et al., 2001;
Manning-Bo et al., 2002). Furthermore, exposure of mice to
either paraquat or the parkinsonism-inducing toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is followed by an
upregulation of -synuclein that appears to be part of a neuronal
response to toxic insults (Vila et al., 2000; Manning-Bo et al.,
2002). Finally, -synuclein-containing aggregates have been observed
in two animal models of selective nigrostriatal degeneration, one
induced by exposure of rats to rotenone (Betarbet et al., 2000) and the
other caused by injections of mice with paraquat (Manning-Bo et
al., 2002; McCormack et al., 2002).
The features of dopaminergic cell injury accompanied by -synuclein
upregulation and deposition, which characterize mice exposed to
paraquat, make this experimental model particularly suitable for
investigation into the role of -synuclein in neurotoxic processes. In the present study, we tested the hypothesis that increased -synuclein levels may affect paraquat neurodegeneration by comparing paraquat-induced dopaminergic cell loss and protein aggregation in mice
with and without transgenic -synuclein overexpression.
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Materials and Methods |
Animals. Experiments were performed using transgenic
mice that overexpressed either human wild-type -synuclein or a
mutant form of the human protein with an Ala53Thr substitution in the amino acid sequence. This mutation is associated with parkinsonism in
rare familial cases of the disease (Polymeropoulos et al., 1997). Both
lines of transgenic animals have been characterized previously
(Matsuoka et al., 2001). They express high levels of -synuclein
within catecholaminergic neurons under the regulatory control of the
tyrosine hydroxylase (TH) promoter and do not develop any overt
spontaneous pathology. Transgenic animals of 3-4 months of age were
injected intraperitoneally with either saline or paraquat at the dose
of 10 mg/kg once a week for 3 consecutive weeks. Control littermates
were also treated with saline or paraquat. Animals were killed by
cervical dislocation at 1 week after the last injection. Experimental
protocols were in accordance with the National Institutes of Health
guidelines for use of live animals and were approved by the Animal Care
and Use Committee at The Parkinson's Institute.
Histochemistry and cell counting. After removal of the
brains, midbrain blocks were immersion fixed in 4% paraformaldehyde and cryoprotected in sucrose. Serial coronal sections (40 µm) were
cut on a cryostat, collected in cryopreservative, and stored. Midbrain
sections containing the substantia nigra at the level of the third
nerve were used for silver staining. Sections were rinsed of
cryoprotectant solution and then incubated in proprietary reagents per
manufacturers instructions (FD Neurotechnologies, Ellicott City, MD),
mounted on gelatin-coated slides, dehydrated, and coverslipped. For
stereological cell counting, coronal midbrain sections were
immunostained with an antibody against TH (1:800; Pel Freez
Biologicals, Rogers, AR) and counterstained with 0.5% Cresyl violet.
After delineation at low magnification, every sixth section throughout
the substantia nigra pars compacta was sampled at high magnification
(cast grid system; Olympus, Albertslund, Denmark). Neurons
were counted using the optical fractionator method, an unbiased
quantitative technique that is independent of neuronal size and shape
and any conformational changes in the tissue (West et al., 1991;
McCormack et al., 2002). In experiments in which the number of neurons
containing -synuclein aggregates was estimated, sections at the
level of the third nerve were incubated with anti--synuclein (1:200;
Chemicon International, Temecula, CA) and
anti-neuron-specific nuclear protein (NeuN) (1:200; Chemicon International), followed by rabbit anti-sheep-FITC
(Jackson ImmunoResearch Laboratories, West Grove, PA) and
goat anti-mouse-Cy3 (Chemicon International), and mounted
in Anti-Fade medium (Molecular Probes, Eugene, OR).
Sections were observed using a Nikon light microscope equipped for epifluorescence, and neurons were counted in the substantia nigra pars compacta. Data were expressed as number of
NeuN-positive cells containing -synuclein-immunoreactive
aggregates/total number of NeuN-positive cells × 100. For
confocal microscopy, tissue sections were blocked in Mouse on Mouse
Monoclonal blocking reagent (Vector Laboratories,
Burlingame, CA) before overnight incubation at 4°C with
anti--synuclein (1:200; Transduction Laboratories, Lexington, KY), followed by immersion in goat anti-mouse-FITC (Jackson ImmunoResearch Laboratories). Sections were
counterstained with Hoechst bisbenzimide and observed using the
Zeiss-LSM5 Pascal confocal microscopy system. For
dual-labeled immunofluorescence, overnight incubation at 4°C with
anti--synuclein (1:200; Transduction Laboratories) and
anti-HSP70 (SPA-812 1:200; StressGen, Vancouver, Canada)
was followed by immersion in goat anti-mouse-FITC and goat
anti-rabbit-Cy-3 (both from Jackson ImmunoResearch
Laboratories).
Immunoblotting. Brain samples from the ventral mesencephalon
and the cerebellum were dissected on ice, sonicated in lysis buffer
with protease inhibitors, and after centrifugation, the supernatant
fraction was decanted. Protein extracts were separated by SDS gel
electrophoresis, and proteins were transferred to nitrocellulose. Blots
were blocked and incubated overnight with anti-HSP70 (sc-24 1:500;
Santa Cruz Biotechnology, Santa Cruz, CA) or SPA-812
(1:1000; StressGen) or anti-synaptophysin (1:10,000;
Dako, Carpinteria, CA). Synaptophysin immunoreactivity was
used for assessing equal protein loading.
Statistical analysis. Differences among means were analyzed
using one-way ANOVA. Newman-Keuls post hoc analysis was
used when differences were observed in ANOVA testing
(p < 0.05).
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Results |
Effect of -synuclein overexpression on
paraquat-induced neurodegeneration
Silver staining was used as a marker for degenerating neurons to
compare paraquat neurotoxicity in overexpressing mice versus controls.
In control animals, no silver staining was observed after saline
injections, whereas scattered injured neurons containing silver grains
were present throughout the substantia nigra pars compacta of animals
exposed to paraquat (Fig.
1A,C). Results in overexpressing mice were substantially different in that midbrain sections showed no silver staining regardless of whether these transgenic animals had been exposed to paraquat or injected with saline
(Fig. 1B,D). This lack of pathology provided initial
evidence that increased -synuclein expression conferred resistance
to paraquat-induced neurodegeneration.
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Figure 1.
Effect of -synuclein overexpression on
paraquat-induced neurodegeneration. Silver staining of the substantia
nigra pars compacta of control (A, C) and
-synuclein-overexpressing (B, D) mice injected with
saline (A, B) or paraquat (C, D). Animals
were treated once a week for 3 consecutive weeks and killed at 7 d
after the last injection of saline or paraquat. The arrow in
C indicates silver grain deposition in a degenerating
neuron, and the inset represents a higher magnification image of
this neuron. Sections shown in this figure were obtained from mice
overexpressing human wild-type -synuclein and corresponding
controls. Similar results, however, were observed when saline or
paraquat was administered to mice overexpressing human Ala53Thr mutant
-synuclein and littermate controls. Scale bar, 25 µm.
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The effect of paraquat on the survival of dopaminergic cells was then
evaluated directly by stereological counts of TH-immunoreactive neurons. Consistent with previously reported findings in C57BL/6 mice
(McCormack et al., 2002), the number of TH-positive cells was
significantly reduced by 25-35% in the substantia nigra pars compacta
of control mice at 7 d after the last of three weekly paraquat
injections (Table 1). That this loss of
TH-immunoreactive cells was caused by actual degeneration of
dopaminergic neurons rather than a mere downregulation of the TH marker
was demonstrated by counting the number of nigral Nissl-stained neurons
and showing that this number was also significantly decreased by
paraquat in non-overexpressing mice (Table 1). Quite in contrast, when TH-positive and Nissl-stained neurons were evaluated in the substantia nigra pars compacta of overexpressing mice, no cell loss was found, and
nigral counts were similar in animals treated with paraquat as compared
with saline (Table 1). It is noteworthy that complete protection
against paraquat-induced neurodegeneration, as assessed by silver
staining and cell counting, was observed in both lines of transgenic
mice used for these studies, i.e., animals overexpressing human
wild-type -synuclein and transgenic mice with human Ala53Thr mutant
-synuclein (Fig. 1, Table 1).
Paraquat-induced -synuclein aggregation
In C57BL/6 mice, paraquat has been reported to cause not only
dopaminergic cell degeneration but also the intraneuronal
deposition of -synuclein-containing aggregates
(Manning-Bo et al., 2002). We therefore compared
paraquat-induced -synuclein assembly in control and overexpressing
mice and assessed whether protection against neurodegeneration in the
latter experimental group was accompanied by significant changes in
protein deposition. In midbrain sections from control mice injected
with saline, -synuclein immunoreactivity was diffuse throughout the
substantia nigra and stained mostly neuronal fibers (Fig.
2A). In saline-treated overexpressing animals, confocal
microscopy showed -synuclein immunoreactivity within nigral cell
bodies (Fig. 2B). This
effect was most likely a consequence of -synuclein overexpression
driven by the TH promoter because colocalization was found after
labeling these cells with antibodies against -synuclein and TH (data
not shown). Paraquat exposure caused the accumulation of intracellular
-synuclein-immunoreactive deposits. These paraquat-induced
aggregates were observed in both control and overexpressing mice with
no overt differences in their histological characteristics and
distribution (Fig. 2C,D). The number of neurons containing
aggregates was counted in the substantia nigra pars compacta at the
level of the third nerve and found to be 29.5 ± 2.2 (SEM) and
36.3 ± 3.0% of the total neuronal count in paraquat-exposed
control and overexpressing mice, respectively.
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Figure 2.
Paraquat-induced -synuclein deposition in
control and -synuclein-overexpressing mice. Confocal images of
neurons in the substantia nigra pars compacta of control (A,
C) and -synuclein-overexpressing (B, D) mice
injected with saline (A, B) or paraquat (C,
D). Midbrain sections were stained with an antibody against
-synuclein and counterstained with Hoechst bisbenzimide. Arrows in
C and D indicate -synuclein-positive
deposits. Sections shown in this figure were obtained from mice
overexpressing human Ala53Thr mutant -synuclein and corresponding
controls. Similar results, however, were observed when saline or
paraquat was administered to mice overexpressing human wild-type
-synuclein and littermate controls. Scale bars, 10 µm.
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-Synuclein overexpression and HSP70
Chaperone proteins and, in particular, HSP70 have been reported to
play a protective role against paraquat toxicity (Ding and Keller,
2001; Minois, 2001). We therefore tested the hypothesis that chaperones
may also contribute to the resistance of transgenic mice to paraquat by
comparing HSP70 levels in -synuclein-overexpressing mice versus
control animals. In the former, more pronounced HSP70-immunorective bands were observed by Western blot analysis of midbrain homogenates (Fig. 3A). This increase in
HSP70 was observed only in catecholaminergic brain regions (e.g., in
the ventral mesencephalon, but not in the cerebellum), thus supporting
its association with the TH-driven -synuclein transgenic expression
(Fig. 3A,B). Additional evidence of -synuclein-dependent
changes in HSP70 was obtained from histological observations. Midbrain
sections from overexpressing and control animals were immunostained
with antibodies against HSP70 and -synuclein. Transgenic mice showed
enhanced HSP70 immunoreactivity and colocalization of -synuclein and
HSP70 within neurons of the substantia nigra (Fig.
3C-H).
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Figure 3.
Enhanced HSP70 levels in -synuclein
overexpressing mice. Western blot analysis of HSP70 and synaptophysin
immunoreactivities in homogenates from the ventral mesencephalon
(A) and cerebellum (B) of
control animals and transgenic mice overexpressing human wild-type
-synuclein is shown. C-H, Midbrain sections from
control animals (C-E) and mice overexpressing
human Ala53Thr mutant -synuclein (F-H) were
immunostained with antibodies against -synuclein (C,
F) and HSP70 (D, G). Merged images
(E, H) show colocalization within nigral cell
bodies of overexpressing animals (H).
Scale bar, 100 µm.
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Discussion |
Results of this study provide the first evidence in an animal
model that increased expression of -synuclein can prevent
toxicant-induced dopaminergic cell degeneration. This neuroprotective
effect is apparently at odds with findings in other experimental
systems that indicated a relationship between -synuclein and
neuronal injury. For example, transgenic -synuclein expression has
been reported to cause both pathological inclusions and
neurodegeneration in Drosophila (Feany and Bender, 2000;
Auluck et al., 2002), and consistent with a deleterious role of the
protein, lack of -synuclein protected knock-out mice against the
neuronal loss triggered by the toxicant MPTP (Dauer et al., 2002).
Earlier evidence, however, also suggests that increased levels of
-synuclein do not necessarily lead to neurotoxicity, because
-synuclein overexpression in transgenic mice does not consistently
induce neuronal damage (Masliah et al., 2000; Matsuoka et al., 2001),
nor does it exacerbate neurodegeneration caused by MPTP
(Rathke-Hartlieb et al., 2001). Finally, findings in vitro
have raised the possibility that -synuclein may play a protective
role. Neuronal cell lines transfected with -synuclein were resistant
to hydrogen peroxide-induced oxidative stress as well as to apoptotic
stimuli (da Costa et al., 2000; Hashimoto et al., 2002), and primary
mesencephalic cultures isolated from -synuclein null mice were more
susceptible to dopaminergic cell loss caused by rotenone (Dauer et al.,
2002). The involvement of -synuclein in protective mechanisms would
also be in line with observations during brain development (Clayton and
George, 1998; Hsu et al., 1998) and in models of developmental target injury (Kholodilov et al., 1999a,b), suggesting a relationship between
-synuclein expression and neuronal plasticity and recovery. Taken
together, our current results and previous data indicate that the toxic
consequences of -synuclein expression may vary quite significantly
under different conditions. Because of this variability, it is
conceivable that -synuclein participates in both toxic and
protective pathways and that its involvement in human neurodegenerative
processes may arise from a gain of toxic function as well as a loss of
defensive properties.
A comparison of paraquat neurotoxicity in mice with transgenic
expression of human wild-type versus Ala53Thr mutant -synuclein revealed no differences, because both lines of overexpressing animals
displayed complete absence of dopaminergic cell death. This finding
supports the interpretation that, at least in the mouse model,
neuroprotection is associated more strictly with increased protein
levels and is less dependent on the expression of different forms of
-synuclein. As a possible mechanism of -synuclein
neuroprotection, we also assessed the relationship between dopaminergic
cell damage and -synuclein aggregation. Paraquat exposure induced
the formation of -synuclein-containing deposits. This effect,
however, was seen in both control and overexpressing mice, i.e., in the
presence and absence of neurodegeneration, thus suggesting that
neuroprotection is not a mere consequence of lack of protein deposition.
The precise mechanisms involved in -synuclein neuroprotection remain
unclear. -Synuclein itself may possess properties that counteract
toxic injury, and its expression could affect specific stress-signaling
pathways linked to neuronal survival. For example, Hashimoto and
colleagues (2002) have recently suggested that -synuclein expression
could confer resistance to in vitro hydrogen peroxide toxicity via the inactivation of c-Jun N-terminal kinase, a member of
the mitogen-activated protein kinase family. A consistent feature associated with the TH-driven expression of either human wild-type or
mutant -synuclein in our resistant mice was an increased level of
HSP70 within dopaminergic neurons. Because this chaperone plays a role
in protein-induced stress responses (Bukau and Horwich, 1998), it is
quite possible that its increase may represent an adaptive change to
high intraneuronal -synuclein concentrations. Enhanced expression of
HSP70 has been shown to be neuroprotective in a Drosophila
model of Parkinson-like pathology (Auluck et al., 2002). In this model,
HSP70 suppressed neurodegeneration without affecting the formation of
-synuclein-containing inclusions, a finding that bears interesting
similarities to our current observation of neuronal survival in the
presence of protein deposition. Transgenic flies carrying extra copies
of HSP70 have also been found to be relatively resistant to paraquat
toxicity (Minois, 2001). Moreover, a role of chaperones against the
damaging effects of the herbicide is supported by in vitro
studies in which neuronal cell lines stably transfected with heat-shock
proteins were less vulnerable to paraquat-induced impairment of
proteasomal activity and decrease in cell viability (Ding and Keller,
2001). Overall, these data indicate that higher levels of HSP70 could
conceivably contribute to neuroprotection after paraquat exposure to
-synuclein transgenic mice. Paraquat is known to trigger toxic
oxidative reactions (Cohen, 1994), and chaperones like HSP70 could
prevent its toxicity by counteracting oxidative damage to proteins and
facilitating the degradation of oxidized proteins through the
proteasomal system (Grune et al., 1997; Okada et al., 1999; Ding and
Keller, 2001).
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FOOTNOTES |
Received Dec. 9, 2002; revised Jan. 17, 2003; accepted Jan. 21, 2003.
This work was supported by National Institutes of Health Grants ES10442
and ES10806, the Backus Foundation, the Lookout Fund, and
Mylan Pharmaceuticals. We thank Drs. John Hardy, Matthew
Farrer, and Karen Duff for their kind donation of -synuclein
transgenic founders, Drs. Serge Przedborski and Michael Lee for helpful
discussions, and Su Cumine and Mitra Lavasani for technical assistance.
Correspondence should be addressed to D. A. Di Monte, The
Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089-1605. E-mail: ddimonte{at}parkinsonsinstitute.org.
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TOP
ABSTRACT
Introduction
