Time course and progression of wild type α-Synuclein accumulation in a transgenic mouse model
- David Amschl†1,
- Jörg Neddens†1,
- Daniel Havas1,
- Stefanie Flunkert1,
- Roland Rabl1,
- Heinrich Römer2,
- Edward Rockenstein3,
- Eliezer Masliah3,
- Manfred Windisch1 and
- Birgit Hutter-Paier1Email author
© Amschl et al.; licensee BioMed Central Ltd. 2013
Received: 10 July 2012
Accepted: 3 January 2013
Published: 9 January 2013
Progressive accumulation of α-synuclein (α-Syn) protein in different brain regions is a hallmark of synucleinopathic diseases, such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. α-Syn transgenic mouse models have been developed to investigate the effects of α-Syn accumulation on behavioral deficits and neuropathology. However, the onset and progression of pathology in α-Syn transgenic mice have not been fully characterized. For this purpose we investigated the time course of behavioral deficits and neuropathology in PDGF-β human wild type α-Syn transgenic mice (D-Line) between 3 and 12 months of age.
These mice showed progressive impairment of motor coordination of the limbs that resulted in significant differences compared to non-transgenic littermates at 9 and 12 months of age. Biochemical and immunohistological analyses revealed constantly increasing levels of human α-Syn in different brain areas. Human α-Syn was expressed particularly in somata and neurites of a subset of neocortical and limbic system neurons. Most of these neurons showed immunoreactivity for phosphorylated human α-Syn confined to nuclei and perinuclear cytoplasm. Analyses of the phenotype of α-Syn expressing cells revealed strong expression in dopaminergic olfactory bulb neurons, subsets of GABAergic interneurons and glutamatergic principal cells throughout the telencephalon. We also found human α-Syn expression in immature neurons of both the ventricular zone and the rostral migratory stream, but not in the dentate gyrus.
The present study demonstrates that the PDGF-β α-Syn transgenic mouse model presents with early and progressive accumulation of human α-Syn that is accompanied by motor deficits. This information is essential for the design of therapeutical studies of synucleinopathies.
KeywordsBehavior Immunofluorescence Motor deficit Mouse model Parkinson’s disease Phosphorylation Synucleinopathy α-Synuclein Transgene
Synucleinopathic diseases, like Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), are all characterized by a pathologic aggregation of α-Synuclein (α-Syn) protein in distinct brain regions (reviewed by ). Increased expression of α-Syn can be caused by a dominant heritable form of PD due to duplication or triplication of the α-Syn gene [2–4]. In order to model such synucleinopathies in vivo different mouse models were developed that overexpress human wild type α-Syn (hα-Syn) [5–12]. When expression is driven by the murine Thy1 promoter, transgenic mice accumulate wild type hα-Syn in cortical and subcortical regions including the nigrostriatal system [6, 13] whereas under the human PDGF-β promoter hα-Syn accumulates preferentially in the neocortex and limbic system (D-Line) .
Abnormal accumulation of hα-Syn in D-Line transgenic mice is accompanied by alterations in mGluR5 and autophagy similar to what has been observed in patients with dementia with Lewy bodies [14, 15]. Moreover the behavioral and neurodegenerative pathology in D-Line mice can be reversed with mGluR5 antagonists  or by promoting the clearance of α-Syn with rapamycin , Beclin 1 [16, 17] and neurosin . Given the behavioral phenotype and the predominant accumulation of α-Syn in the neocortex and limbic system, these studies suggest that the PDGF-β hα-Syn transgenic mouse model reproduces some aspects of synucleinopathies such as DLB. Recent studies have tested compounds developed to ameliorate PD-like pathology in the D-Line mouse model and were able to show a reduction in the accumulation of α-Syn, total and oxidized α-Syn levels and behavioral deficits [19–22].
Taken together, these results indicate that this transgenic model might be useful for studies of α-Syn target validation. However, the progression of the behavioral deficits and pathology in D-Line mice has not been fully characterized. For this purpose we investigated the time course of behavioral deficits and neuropathology in D-Line mice. The occurrence of motor deficits was investigated using a challenging beam walk paradigm. We also quantified hα-Syn expression in the hippocampus and striatum using a biochemical approach. Moreover, by quantitative immunofluorescence at different ages we compared expression levels of both murine α-Syn and hα-Syn in the cortex, hippocampus, striatum and substantia nigra relative to non-transgenic littermates. Furthermore, we identified several cell populations that express transgenic hα-Syn in different areas of the adult brain.
Progressive motor deficits of D-Line mice
The nest building test was used to analyze D-Line mice compared to non-transgenic littermates at 9 months of age. D-Line mice showed a significantly reduced nest building behavior (Figure 1D). While non-transgenic mice built an almost perfect nest with the provided material, the D-Line mice shredded only about 50% of the nesting material and an easily identifiable nest site was missing. Since no significant differences between male and female D-Line mice were observed (data not shown), data of both sexes were pooled for Figure 1D. Taken together, our behavioral analysis argues for an impairment of motor coordination in transgenic mice during execution of challenging tasks, whereas overall motor activity is largely unaffected.
Quantification of α-synuclein protein levels over age
Distribution pattern of human, murine and phosphorylated α-synuclein protein
Identification of α-synuclein-expressing neurons
This study was designed to characterize the time course and progression of the pathology in D-Line mice, a model of α-Syn accumulation similar to DLB. We found progressive motor coordination deficits at 9 and 12 months of age complemented by alterations in the nest building behavior. These deficits were accompanied by a parallel age-dependent increase in the levels of hα-Syn in somata and neuritic processes of a subset of neocortical, limbic and nigrostriatal system cells. The mechanisms by which accumulation of hα-Syn in these circuitries might result in functional deficits are not completely clear. Recent findings on changes in expression levels of neurotrophic factors in hα-Syn transgenic mice  suggest that altered BDNF levels could be linked to onset and progression of Parkinson’s disease .
The progressive motor alterations in the challenging beam walk test detected in D-Line mice are consistent with previous studies using the rotarod and pole test [5, 15] and support a dysfunction of the nigrostriatal system. Also supporting this possibility, previous studies have shown that D-Line mice of either sex generally perform worse compared to non-transgenic littermates; however, at the age of 9 months D-Line and non-transgenic male mice consistently slip more often during the challenging beam walk test than females. In transgenic mice the sex difference seems to increase up to the age of 9 months, suggesting that hα-Syn has an earlier impact on motor performance in male than in female mice. Interestingly, these results are reminiscent of sex differences in humans where female Parkinson patients show a delayed onset of the disease compared to males .
Nest building behavior is an intrinsic behavior in both female and male mice that requires proper fine motor skills. The nest is important for sustaining body temperature and provides shelter during birth and rearing of offspring. Different lesioning studies provide evidence that nest building behavior strongly depends on the proper function of the hippocampus, caudate putamen and ventral mesencephalic tegmentum [40–42]. Moreover, nest building was shown to be dopamine- and enkephalin-dependent . All these brain systems are known to be highly relevant for PD [44, 45], suggesting that the nest building test is an appropriate tool for assessing Parkinson-associated impairments. Therefore, our here presented data of nest building and motor deficits in the beam walk test suggest, that D-Line transgenic mice represent with the most common behavioral symptoms of PD.
Analyses of hα-Syn levels in the brain by ELISA showed an age dependent increase of transgenic protein levels in the hippocampus and striatum between 3 and 12 months. Using quantitative analysis of immunofluorescence against hα-Syn we could verify this result in situ. Interestingly, however, we detected neither genotype-dependent nor age-dependent increases in total (human and murine) α-Syn levels. Given that under the PDGF-β promoter the mRNA expression of α-Syn is stable throughout life, the progressive accumulation of hα-Syn protein in the brains of the transgenic mice indicates deficits in clearance. This is consistent with previous studies showing alterations in the autophagy pathway in the D-line mice [14, 46], these alterations were reversed pharmacologically with rapamycin  or genetically with Beclin-1  or Atg7  and worsen with shAtg7  or Bafilomycin-A1 . In addition, the finding of constant total α-Syn levels despite the parallel accumulation of transgenic hα-Syn protein raises the possibility that the expression of endogenous murine α-Syn might be a tightly regulated mechanism. Overexpression of hα-Syn could therefore be a trigger for homeostatic downregulation of the murine isoform. Moreover, total α-Syn immunoreactivity even decreased slightly in the substantia nigra of non-transgenic animals suggesting that reduction of α-Syn levels in the nigrostriatal dopaminergic pathway of older mice is a normal event during aging in healthy rodents, consistent with reports by other groups [47, 48].
We identified subsets of transgene expressing neurons as inhibitory GABAergic interneurons or excitatory glutamatergic pyramidal neurons in cortical areas. With respect to dopaminergic cells, we found co-expression of hα-Syn and tyrosine hydroxylase in many neurons of the olfactory bulb, in contrast to the substantia nigra where only low levels of hα-Syn were detectable. We also detected hα-Syn immunoreactivity in some GABAergic interneurons of the olfactory bulb but, in contrast to cortical areas, not in glutamatergic principal neurons (mitral cells). Overall, this pattern is consistent with the reported expression of PDGF-β in different types of neurons [49, 50]. Our investigation of hα-Syn phosphorylation at residue S129 shows that immunoreactivity is largely restricted to the nuclei of neurons that express high levels of the transgenic protein. Of note, we found no indication of granular or fibrillary-like accumulations of pS129-hα-Syn, opening the question whether this nuclear immunoreactivity reflects regular physiological events or rather indicates progression towards neuropathology consistent with previous reports . Finally, consistent with previous studies  we found that hα-Syn accumulates in areas featuring immature neurons, such as the subventricular zone and the rostral migratory stream. Accumulation of hα-Syn in these areas results in reduced proliferation and survival of neuroblasts , however, the functional relevance of these alterations is yet unknown. Interestingly, we found no indication of hα-Syn immunoreactivity in maturing neurons of the dentate gyrus, indicating that hα-Syn expression is not a common feature of all populations of immature or migrating neurons. Additional studies are required to investigate whether these regional differences have functional relevance that may affect survival rates or maturation of these cells.
Our data suggest that hα-Syn accumulates in subsets of glutamatergic, dopaminergic, and GABAergic, neuronal populations in the neocortex, limbic system and nigrostriatal system similar to the distribution of hα-Syn in DLB. Immunoreactivity for human protein phosphorylated at residue S129 is restricted to neuronal somata, whereas much of the additional immunofluorescent signal from hα-Syn protein not phosphorylated at the S129 residue comes from areas with few neuronal somata but dense neuropil, thus mimicking the distribution of the endogenous murine α-Syn isoform. We also detected progressively increasing levels of hα-Syn protein during adulthood using different experimental approaches, and concomitant impairment of motor coordination. In contrast, the level of total α-Syn is constant between 3–12 months, possibly due to a compensatory downregulation of the endogenous α-Syn isoform. We conclude that different readouts, i.e. behavioral, biochemical and histological, can detect structural and functional pathology in the D-Line mouse model, and that this animal model is highly valuable for PD-related research and drug development.
For this study we used male and female mice over-expressing human wild type α-Syn under the regulatory control of the platelet-derived growth factor (PDGF-β) promoter with a C57BL/6xDBA background (D-Line, ). All experiments were performed with hemizygous D-Line mice and corresponding non-transgenic littermates. Animals were housed in individually ventilated cages on standardized rodent bedding (Rettenmayer®). The room temperature was kept at approximately 24°C and the relative humidity between 40-70%. Mice were housed under constant light-cycle (12 hours light/dark). Dried pelleted standard rodent chow (Altromin®) and normal tap water were available to the animals ad libitum. The health and well-being of each individual animal was monitored regularly. Animal studies conformed to the Austrian guidelines for the care and use of laboratory animals and were approved by the Styrian Government, Austria.
For behavioral tests 6, 9 and 12 months old animals were used. 12 males (6 tg and 6 ntg) and 12 females (6 tg and 6 ntg) were analyzed per age group. The challenging beam walk test was carried out with all mice as previously described . In short, mice were trained to traverse the length of a beam starting at the widest section and ending at the narrowest, most difficult section. The narrow end of the beam led directly into the animal’s home cage. Mice received two days of training before testing. In order to increase difficulty on the day of testing, a wire mesh of corresponding width was placed over the beam. On the testing day mice were required to run five trials. Mice were video-taped while traversing the grid-surfaced beam. Videotapes were viewed and rated in slow motion for slips, number of steps, slips per step and time to traverse. After normal distribution was verified by Kolmogorov-Smirnov test, group differences were calculated by one-way ANOVA, two-way ANOVA followed by Bonferroni’s post hoc test, factors transgene, gender and time, and unpaired t-test, using GraphPad Prism 4.03.
To test the individual nest building behavior, 9 months old mice were housed separately overnight in cages containing wood chip bedding and one 5 cm square piece of pressed cotton (nestlet). No other nesting material was provided. The nestlet was introduced on the day before the evaluation of the nest. The following morning the nest was assessed, according to a five-point scale . If the nestlet was not noticeably touched it was scored with 1 point. A near perfect nest, in which at least 90% of the nestlet was used, was scored with 5 points. After normal distribution was unconfirmed by Kolmogorov-Smirnov test, group differences were calculated by Mann–Whitney U-test, using GraphPad Prism 4.03.
Mice were deeply anesthetized by Isoflurane (BAXTER®, Austria) and the thorax was opened to excavate the heart. Animals were flush-perfused transcardially with 0.9% saline through the left ventricle. The hemispheres were divided at midline. The right hemisphere was immersion fixed in 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4, for 1 h at room temperature (RT), cryoprotected in 30% sucrose, and snap-frozen in dry ice-cooled isopentane for further histological evaluations. The left hemisphere was dissected into hippocampus, striatum and rest brain, shock-frozen on dry ice, and stored at −80°C for biochemical hα-Syn determination.
We analyzed expression levels of hα-Syn in the hippocampus and striatum of D-Line mice and non-transgenic littermates at different ages: D-Line: 3, 9 and 12 months (n = 6), 6 months (n = 5); ntg: 6 months (n = 1). Total protein was extracted from brain samples by homogenization in 8 volumes guanidine buffer (5 M guanidine HCl, 50 mmol/L TrisHCl, pH 8.0). The homogenates were mixed for 4 h at RT. Samples were then diluted 500x (hippocampus), 100x (striatum) with cold reaction buffer (2.68 mmol/L KCl, 1.47 mmol/L KH2PO4, 136.89 mmol/L NaCl, 8.1 mmol/L Na2HPO4, 5% BSA, 0.03% Tween-20 and protease inhibitor cocktail) and centrifuged at 16.000 g for 20 min at 4°C. Supernatants were analyzed for total hα-Syn concentrations by ELISA (Hu α-Synuclein ELISA Kit #KHB0061, Invitrogen) following the manufacturer’s protocol. Group differences were statistically analyzed by excluding outliers using Grubb’s test and subsequent one-way ANOVA followed by Bonferroni’s post hoc test, using GraphPad Prism 4.03.
We quantitatively investigated tissue obtained from mice at different ages (Figures 3–4). D-Line / ntg: 3 months (n = 8 / 4); 6 months (n = 9 / 4); 9 months (n = 6 / 5); 12 months (n = 8 / 3). A natural α-Syn knockout line from Harlan (C57BL/6JOlaHsd) served as negative control to test for antibody specificity (Additional file 1).
Qualitative multichannel immunofluorescence experiments (Figures 5–9) were performed at RT on sagittal cryosections (10 μm thick; systematic uniform random sampling) of adult mice (age 9 months, n = 3 per genotype, mixed sex) using the following protocol: Wash cryosections 2 × 5 min in 0.05 M tris-buffered saline (TBS, pH 7.6) with 0.25% Triton X-100, block 1 h with MOM blocking reagent (Vector, Burlingame, CA), wash 2 × 2 min, incubate 5 min in MOM diluent, incubate 40 h at 4°C in new MOM diluent with primary antibodies, wash 3 × 5 min, incubate secondary antibodies 1 h in MOM diluent wash 3 × 5 min, mount with Mowiol.
List of primary antibodies
Enzo Life Sciences, Plymouth Meeting, PA
Human phospho α-Synuclein
Abcam, Cambridge, UK
Santa Cruz Biotechnology, Santa Cruz, CA
Santa Cruz Biotechnology
ProteinTech Group, Chicago, IL
Novus Biologicals, Cambridge, UK
Millipore, Temecula, CA
LabVision, Fremont, CA
Buonanno Lab, NIH; Vullhorst et al., 2009
Secondary antibodies donkey anti-rat, donkey anti-mouse, donkey anti-rabbit, and donkey anti-goat were labeled with Cy2/DyLight488, Cy3, or Cy5/DyLight649 fluorophores (Jackson ImmunoResearch, West Grove, PA); all secondary antibodies were highly cross-adsorbed (ML quality) to prevent unspecific cross-reactivity. Specificity of secondary antibodies was assessed by omitting primary antibodies on parallel section as shown in an additional file (Additional file 1). Controls were routinely executed together with regular experiments.
Images for quantitative analysis were recorded with an Axio mRm camera mounted on AxioImager Z1 epifluorescence microscope at 10x magnification. Exposure time and additional settings were kept constant for all images used in quantification. Camera was set to the linear default. Regions of interest (ROI) were defined by individual delineation of the cortex, hippocampus and substantia nigra, and total α-Syn immunofluorescence signal was determined by integrating pixel intensity throughout the ROI using ImageProPlus Software (Version 6.2). Five sections per brain region were analyzed deriving from five different systematically chosen medio-lateral levels. After normal distribution was verified by Kolmogorov-Smirnov test, group differences in histological variables were calculated by one-way ANOVA followed by Bonferroni’s post hoc test, using GraphPad Prism 4.03. Epifluorescence z-stack images (8–10 z-levels, 0.3 μm apart, 20% overlay) presented in the figures were obtained at 40x magnification and were collapsed using the Extended Focus function in AxioVision (v4.8) software.
dementia with Lewy bodies
v-erb-a erythroblastic leukemia viral oncogene homolog 4
glutamic acid decarboxylase 67 kD
ionized calcium binding adaptor molecule 1/allograft inflammatory factor 1
multiple system atrophy
phospho-S129 human α-synuclein
polysialic acid-neuronal cell adhesion molecule
region of interest
We thank Stefan Duller for his support in planning biochemical experiments and Martina Mitrovic for planning behavioral tests. We also like to thank Andres Buonanno of the NIH for providing the C-ErbB4 antibody. This work was supported by R&D grants of QPS Austria GmbH, and by NIH grants AG18440 and AG022074 (EM).
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