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-synuclein levels in the blood and brain
* Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany;
Physiology Weihenstephan, Technical University Munich, Freising-Weihenstephan, Germany; and
Department of Behavioural Ecology and Evolutionary Genetics, Max Planck Institute for Ornithology, Starnberg (Seewiesen), Germany
2Correspondence: Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Hoppe-Seyler Str. 3, 72076 Tübingen, Germany. E-mail: thomas.gasser{at}med.uni-tuebingen.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-synuclein modulates the risk to develop sporadic Parkinson’s disease (PD). Whether this is mediated by regulating -synuclein expression levels remains unknown. Therefore, we analyzed levels of -synuclein in blood and human post mortem brain tissue including the substantia nigra using quantitative real-time reverse transcriptase-polymerase chain reaction and enzyme linked immunosorbent assay in vivo. Single nucleotide polymorphism (SNP) rs356219, a tagging SNP for a disease-associated haplotype in the 3' region of the SNCA gene, has a significant effect on SNCA mRNA levels in the substantia nigra and the cerebellum. Further, the "protective" genotype 259/259 of the PD-associated promoter repeat NACP-Rep1 is associated with lower protein levels in blood than genotypes 261/261, 259/261, and 259/263. In conclusion, we provide evidence that -synuclein levels are influenced by genetic variability in the promoter and 3' region of the SNCA gene in vivo.—Fuchs, J., Tichopad, A., Golub, Y., Munz, M., Schweitzer, K. J., Wolf, B., Berg, D., Mueller, J. C., Gasser, T. Genetic variability in the SNCA gene influences -synuclein levels in the blood and brain.
Key Words: Parkinson’s disease • SNP • NACP-Rep1 • substantia nigra • gene expression • real-time RT-PCR • ELISA
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-synuclein, in familial and sporadic Parkinson’s disease (PD). -Synuclein is a major component of Lewy bodies, a pathological hallmark of sporadic PD (sPD) (1)
. Further, point mutations in the SNCA gene (2
, 3)
as well as multiplications of wild-type SNCA (4
5
6
7
8
9)
cause PD in rare families. These SNCA multiplications strikingly demonstrate that overexpression of wild-type -synuclein is sufficient to cause parkinsonism in a dose-dependent manner (5
, 7)
. Multiplication carriers with three SNCA copies (duplication on one of the chromosomes) show a 1.5-fold increase in RNA and protein levels, whereas four SNCA copies (triplication) lead to a 2-fold increase (5)
. These findings raise the very important question whether modest, but chronic, overexpression of -synuclein could contribute to the pathogenesis of sPD, if not in all, then at least in a subset of patients.
Contradictory evidence exists with regard to a correlation of expression levels of -synuclein with disease status (PD vs. controls) with both positive (10
11
12)
and negative (13
14
15)
correlations. One potential reason for these inconsistencies could be that differences in expression levels of -synuclein might not only be dependent on disease status but might also be modified by genetic variability, i.e., in the SNCA gene itself.
Several studies (16
17
18)
have now shown that genetic variation in the promoter region of the SNCA gene modulates the risk for sPD, including a recent meta-analysis that confirmed that NACP-Rep1 promoter alleles are significantly associated with disease (19)
. We have previously characterized the linkage-disequilibrium (LD) -structure of the -synuclein gene and performed an association analysis with sPD (20)
. We found one LD-block in the 3' region of SNCA to be strongly associated with PD, which was recently independently confirmed in the Japanese population (21)
. Support for a role of SNCA alleles in the regulation of SNCA expression so far comes solely from in vitro studies (22)
where a fragment of the SNCA promoter including different alleles of the NACP-Rep 1 repeat led to differences in expression levels of a reporter gene in a neuroblastoma cell line.
Here, we therefore address the important question whether genetic variability in the -synuclein gene (promoter and 3'region) might modulate the risk to develop sPD by influencing the expression levels of -synuclein in vivo in blood and brain. We quantified -synuclein mRNA and protein levels in peripheral blood momonuclear cells (PBMCs) and in four brain regions differentially affected by the neurodegenerative process (substantia nigra, medulla oblongata, cingulate gyrus, and cerebellum) and genotyped PD risk-associated polymorphisms in the SNCA gene in the same individuals.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-Synuclein is expressed in several cells in peripheral blood including mononuclear cells (23)
as well as in platelets (13)
and is secreted into plasma (24)
. We chose to use PMBCs, because several studies (25
, 26)
in blood lymphocytes suggested that these cells might represent a model system for disease-related dysfunctions in PD since these cells express dopamine, dopamine transporter (DAT), and tyrosine hydroxylase (TH). Additionally, lymphocytes of sPD patients display a deregulation in two systems related to PD pathogenesis, dopamine synthesis and signaling (26
27
28)
, as well as mitochondrial function (29)
.
Blood was drawn after informed consent from 115 subjects [mean age 64 yr (range 36–81); 56 females, 59 males], of which 36 were sPD patients and 79 neurologically healthy controls. All controls and PD patients were examined by specialists in movement disorders, and diagnoses were made according to the UK Parkinson’s Disease Society Brain Bank criteria (30)
. sPD was diagnosed only in the absence of a positive family history. The majority of controls were the unaffected spouses of PD patients, diminishing the effect of environmental factors on gene expression. All controls were examined by a specialist in movement disorders and found neurologically healthy. The project was approved by the Ethics Committee of the Faculty of Medicine of the University of Tübingen.
Human post mortem tissues
-Synuclein is ubiquitously expressed in the brain. Brain tissue was provided by the Harvard Brain Tissue Resource Center, the Banc de Teixits Neurològics, Universitat de Barcelona-Hospital Clínic, and the German Brain Bank "Brain-Net," adding to an overall sample of 146 brain samples from 17 sPD patients and 24 controls (Table 1
). Controls had neither neurological or psychiatric symptoms nor any signs of conspicuous neuropathology. Potential variables affecting gene expression in the post mortem human brain are age, post mortem interval (PMI), and gender. There were no significant differences between PMI or gender between PD patients and controls. There were no significant differences in age or PMI between genotype groups (rs356219, rs2583988, or NACP-Rep1). Information on pH, another confounding factor, was not available. The project was approved by the Ethics Committee of the Faculty of Medicine of the University of Tübingen.
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RNA and DNA extraction
Total RNA from brain tissue was extracted using the Absolutely RNA Miniprep Kit (Stratagene, La Jolla, CA, USA). RNA quantity was measured at 260 nm on a spectrophotometer (Ultraspec 2100, Amersham, Buckinghamshire, UK). The ratio 260/230 showed values between 1.6 and 2.2 and 260/280 between 1.8 and 2.1, indicating good RNA quality. RNA was extracted from blood leukocytes using the mRNA Isolation Kit for Blood/Bone Marrow (Roche Applied Science, Mannheim, Germany). Human brain DNA was isolated using the Qiagen DNA Extraction Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. Human blood DNA was extracted according to established protocols.
Genotyping
DNA sequences around single nucleotide polymorphism (SNP) rs356219 and rs2583988 were amplified by polymerase chain reaction (PCR). A "SNaPshot reaction" was performed with the ABI PRISM SNaPshot Multiplex Kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer’s protocol. Capillary electrophoresis was performed on an ABI 3100 Genetic Analyzer (Applied Biosystems), and the size of the product determined using the GeneScan Size Standard 120LIZ (Applied Biosystems).
To genotype the dinucleotide repeat polymorphism NACP-Rep1, a PCR was performed including one primer labeled with the fluorescent marker Hex. PCR fragments of different size were resolved by capillary electrophoresis on an ABI 3100 Genetic Analyzer (Applied Biosystems). According to the length of the PCR product, the Rep1 genotype was differentiated: allele-1 = 255 bp, allele 0 = 257 bp, allele 1 = 259 bp, allele 2 = 261 bp, and allele 3 = 263 bp, as defined by Xia et al. (31)
and nomenclature adjusted according to http://www.pdgene.org. All SNPs and markers used were tested for Hardy-Weinberg Equilibrium using the http://ihg.gsf.de/cgi-bin/hw/hwa1.pl program. Primer sequences are available on request.
Real-time reverse transcriptase-PCR
Generation of standard curves
For the generation of standard curves for quantitative real-time reverse transcriptase (RT) -PCR, -synuclein cDNA amplicons were generated by PCR (using RZPD clone p998H06114Q3; RZPD, Berlin, Germany), cloned into the pcDNA 3.1 Directional TOPO Expression Vector (Invitrogen, Karlsruhe, Germany), and sequenced. Human neuron-specific enolase 2 (NSE) cDNA was amplified by PCR (using RZPD clone p969F0221D6; RZPD). RNA was transcribed from each plasmid by incubation with T7 polymerase (Roche Applied Science) for 2 h at 37°C after restriction enzyme digestion with XbaI. The RNA was DNaseI digested for 2 h at 37°C and inactivated at 75°C for 5 min, and phenol-chloroform was extracted and quantified using RiboGreen (Invitrogen/Molecular Probes) in a LightCycler RNA quantification application (Roche Applied Science). The dynamic range of the standard curves spanned at least four orders of magnitude.
Endogenous reference genes
Endogenous expressed reference genes were used to correct for variability in initial RNA concentration, for the quality of RNA, and for the efficiency of the reverse transcription reaction. For the relative quantification of -synuclein expression levels in mononuclear blood cells, we used the human porphobilinogen deaminase (hPBGD; LightCycler-h-PBGD Housekeeping Gene Set, Roche Applied Science). hPBGD was run in a multiplex one-tube PCR reaction together with the target gene SNCA. In the human brain, NSE was used to correct for neuronal loss in the tissue of PD patients. For each sample, NSE was amplified within the same run as the target gene SNCA, nonetheless, in separate PCR reactions. Standard curves for the target as well as the reference genes were constructed in independent runs at least four times in order to determine PCR reproducibility and efficiencies. The PCR efficiencies were ESNCA = 1.93, Eh-PBGD = 1.83, and ENSE = 1.85, where E = 2 represents the maximal possible efficiency. PCR conditions and primer sequences are available on request.
RT and real-time PCR
Total RNA (300 ng) from human tissue and 
1 ng of mRNA isolated from blood were used for the RT reaction (Transcriptor, Roche Applied Science). A "no RT" reaction (using water instead of RT) served as a control for the exclusion of genomic DNA contamination. Quantification of -synuclein RNA was performed on a LightCycler (Roche Diagnostics) using the fluorescence resonance energy transfer technique. Gene-specific primers and probes were designed by TibMolBiol (Berlin, Germany). PCR for all standards and samples included cDNA equivalents of 30 ng RNA template (tissue RNA) or a cDNA equivalent of 0.1 ng mRNA template (from blood). The PCR reaction was as follows: 95°C 10 min, 40 cycles: 95°C 10 s, 60°C 10 s, and 72°C 10 s. The second derivative maximum method of quantification was used. Crossing point (Cp) values were analyzed using the LightCycler Relative Quantification Software (RelQuant 1.0, Roche Applied Science). The relative quantification method with inter-run calibrator normalization and efficiency correction was used. The inter-run calibrator is a probe for inter-run comparison with a stable ratio target/reference. It is used for the normalization of all probes within a run and between runs. Samples were assayed in duplicates in at least two independent runs to correct for differences in sample quality and reverse transcription efficiency.
Enzyme linked immunosorbent assay (ELISA)
-Synuclein ELISA was performed using the Human -Synuclein Immunoassay Kit (Biosource Europe, Nivelles, Belgium) according to the manufacturer’s protocol. PBMCs were isolated from 10 ml fresh peripheral venous EDTA-blood by centrifugation on a Ficoll-400 gradient (PAA Laboratories, Cölbe, Germany). Cells from the interphase were collected, washed twice in PBS, and then frozen at –80°C until use. Cells were lysed in 300 µl of cell extraction buffer according to the manufacturer’s protocol. Total protein was measured by a BCA-based protein assay (Pierce BCA Protein Assay Kit, Perbio Science, Bonn, Germany) on a microtiter plate reader (Bio-Rad Model 680, Bio-Rad Laboratories, Munich, Germany). Lysates were used in a 1:50 dilution for the ELISA procedure.
Human brain proteins were extracted using the guanidine-hydrochloride method essentially as described by the manufacturer; 100 mg brain samples were diluted in 8x mass of cold 5 M guanidine-hydrochloride/50 mM Tris-HCL, pH 8.0, and homogenized. Total protein was measured with the BCA method (Pierce BCA Protein Assay Kit, Perbio Science). Homogenates were diluted with cold reaction buffer as follows: 1:150 for samples from cerebellum, 1:100 for samples from cingulate gyrus, 1:50 for substantia nigra and 1:25 for medulla oblongata, and then they were processed according to the manufacturer’s protocol. -Synuclein protein (ng/ml) was normalized to total protein (g/ml) measured in each sample to account for differences in the amount of starting material.
Statistical analysis
Explorative statistical modeling using SAS 9.1 for Windows (SAS Inc., Cary, NC, USA) was used to disclose possible association between explained variable (the RNA/protein level) and the explanatory variable (the SNCA genotype). The level of significance was set at 5%. A log-transformation (log2) was performed in all explained variables to assure Gaussian distribution and to acknowledge the fact that mRNA expression data often do not obey the normal distribution (32)
. The method of general linear model (GLM) was used to evaluate the effect of the primary explained variable (genotype) as well as other secondary variables (disease duration, age at onset, gender, age, and PMI) on the RNA/protein levels. The GLM (33)
is a procedure unifying the ordinary linear regression and ANOVA as well as other procedures based on the least square computation such as ANCOVA. Since some secondary variables also showed a significant effect on the explained variables, they were included in the model as factors (gender) or covariates (disease duration, age at onset, age, and PMI). Where the P value of the maximal model remained significant, an effect of each single term was estimated calculating the type III sum of squares and the corresponding F value and its probability P.
Blood samples
Males with PD were significantly overrepresented compared with females, and the probability to be affected by PD was different across gender (Fisher’s exact test, P<0.01). In the initial step of modeling, the minimal model was built by testing 1) the correlation between protein or mRNA levels and disease duration, age at onset, and age using linear regression; and 2) the effect of gender on -synuclein protein or mRNA levels using ANOVA. Then, the genotype was added to the model to evaluate its additional effect, whereas the secondary variable was maintained in the model as long as the total maximal model remained significant. Thereby, possible influences of secondary variables like gender or disease status could be controlled. Disease-duration-normalized protein values (log residuals of SNCA protein levels) were calculated by regressing on disease duration, thereby defining the time point zero before disease onset. This was achieved by subtracting the predicted value (as defined by the regression line) from each actual data point (representing the -synuclein protein level normalized to total protein).
Brain samples
Brain regions (substantia nigra, cingulate gyrus, cerebellum, and medulla oblongata) were analyzed separately. As for the blood samples, we tested the effects of secondary variables (age, gender, and PMI) on -synuclein protein and mRNA levels. Where the secondary variable contributed significantly to the RNA/protein level explanation, the maximal model was built by adding the genotype to the model.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-synuclein expression levels-synuclein protein increased significantly (linear regression, P=0.02; r2=0.22; Fig. 1
) with disease duration. Thus, protein levels standardized to disease duration were used in subsequent analyses to prevent the confounding effect of disease duration on values obtained for PD patients.
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Effect of secondary variables
Protein levels were significantly positively correlated with age in the cingulate gyrus (P=0.02; n=41; r2=0.13) and significantly negatively correlated with PMI in the cerebellum (P=0.0001; n=41; r2=0.32). In substantia nigra, SNCA/NSE mRNA levels were significantly negatively correlated with age (P=0.02; n=22; r2=0.23) and PMI (P=0.03; n=22, r2=0.21). Although these associations may be partially observed as a result of chance due to multiple testing, the respective covariates age and PMI were included in the ANCOVA.
Effects of genetic variability on -synuclein expression levels
Effect of NACP-Rep1 on -synuclein expression levels in vivo
We first tested the effect of NACP-Rep1 alleles on -synuclein protein and mRNA levels. Individuals with the "protective" genotype 259/259 (n=5) had significantly lower -synuclein protein levels compared with individuals with the 259/261 (n=46; P=0.01), 261/261 (n=48; P=0.002), and 259/263 (n=5; P=0.02) in mononuclear blood cells (Fig. 2
). Genotype 261/261 and 259/259 remained significantly different after adjusting for pairwise multiple comparison of genotypes [Tukey-Kramer honestly significant difference (HSD)], which was performed to ensure an overall significance level of = 0.05. Allele genotype frequencies were well in accordance with previously published results in a collaborative study (19)
.
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Effect of SNP rs2583988 (SNCA promoter) on -synuclein expression levels in vivo
SNP rs2583988 in the promoter of the SNCA gene did not show any correlation to -synuclein mRNA or protein expression.
Effect of SNP rs356219 (3' region SCNA) on -synuclein expression levels in vivo
We then tested for effects of haplotypes in the 3' region of the SNCA gene tagged by SNP rs356219. Genotypes of SNP rs356219 (C/T) showed a significant effect on SNCA mRNA levels in substantia nigra tissue (pwhole model=0.005; prs356219=0.02). The heterozygous genotype CT (n=10) correlates with higher SNCA RNA levels than the protective genotype TT (n=8), which holds true in post hoc testing (adjustment for multiple testing Tukey-Kramer HSD; pCT>TT=0.04; Fig. 3
A). In the cerebellum, SNCA mRNA levels were significantly correlated with SNP rs356219 (pwhole model=0.004; prs356219=0.002). The protective TT genotype showed significantly higher expression levels of SNCA mRNA than the CT and the CC genotype, holding true after adjustment for multiple testing (Tukey-Kramer HSD; pTT>CT=0.002; pTT>CC=0.007; Fig. 3B
). All other regions including blood did not show a significant correlation with any of the genotypes when corrected for the effects of covariates. A summary of the results is listed in Table 2
.
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Effect of disease status on -synuclein RNA and protein levels
We then compared -synuclein protein and mRNA levels between controls and sPD patients. No significant effect of disease status on -synuclein protein (normalized to disease-duration and nonnormalized) and mRNA levels was found in mononuclear blood cells. There was no significant effect of disease status on the RNA/protein levels observed in the substantia nigra, the medulla oblongata, and the cingulate gyrus (data not shown). Only in the cerebellum did disease status have a significant effect on SNCA mRNA levels (P=0.02, ANOVA); PD patients (n=5) had lower mRNA levels than controls (n=5).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-synuclein. We found that genotypes of the NACP-Rep1 repeat length polymorphism in the promoter of the SNCA gene are significantly associated with SNCA protein levels in vivo in blood mononuclear cells, which are considered as a model system for disease-related dysfunctions in PD (25
26
27
28
29)
. The protective NACP-Rep1 genotype 259/259 (meta-analysis: www.pdgene.org) is associated with lower protein levels (4.23 ng/ml) compared with three other genotypes 259/263, 261/261, and 259/263 (on average 4.78 ng/ml) in these cells. It is important to point out, however, that the frequency of the 259/259 genotype is low in the Caucasian population (www.pdgene.org: 6.2% in PD patients and 7.4% in controls), which ultimately results in a low sample size for this genotype also in our study (4.5%). Therefore, the effect, although highly significant, needs to be interpreted with caution and can be taken as a first indication that the effect of NACP-Rep1 on SNCA expression regulation demonstrated in vitro (22)
may also be relevant in vivo.
Furthermore, we found evidence for a regulatory role of the 3' region of SNCA on -synuclein expression in the brain. The heterozygous CT genotype of the SNCA 3' haplotype (defined by the tagging SNP rs356219: CC, risk; TT, protective) is significantly associated with higher mRNA levels compared with the homozygous protective genotype TT in human substantia nigra. In the cerebellum, however, the protective TT genotype is accompanied with higher expression levels compared with CT and CC genotypes. The substantia nigra and the cingulate gyrus are regions affected by PD, while the cerebellum remains mostly preserved. The fact that we found genotype rs356219 associated with mRNA levels in affected and nonaffected brain regions might point to a general and non-tissue-specific regulation of SNCA expression. On the other hand, the heterozygous CT genotype is associated with higher expression levels of mRNA in a PD-affected brain region, while the protective TT genotype is associated with higher expression levels in a nonaffected region. This might indicate that the regulation of expression exerted by this genotype (or any polymorphism in linkage disequilibrium) is a general mechanism but that the fine-tuning of expression regulation might be different in different brain regions and even in different neuronal subpopulations. Our data therefore do not directly support the hypothesis that the protective genotype might be correlated with lower or the risk genotype with higher SNCA expression levels but point nevertheless to a regulatory role of the 3'SNP rs356219 (or any another SNP in LD within the 3' SNCA haplotype) for SNCA expression levels. It is very likely that several effects exerted by genetic variation are acting on the SNCA gene and will, in concert, regulate the expression of -synuclein. Thereby, protective and risk factors might outbalance each other depending on the genetic mosaic of disease-modulating variations in a given individual.
Expression studies have several limitations that need to be considered when interpreting our results. These include 1) sample-related limitations (e.g., limited availability of human brain), different post mortem intervals, age and gender bias, and sampling difficulties (differences in sampling can lead to differences in cell type representation; ref. 10
); and 2) technical limitations (quantification by quantitative RT-PCR and ELISA). If possible, these were addressed in the study design. For example, gender and age bias were limited by including these secondary variables in the statistical model if they showed an effect on SNCA levels. To counterbalance the expected neuronal loss in PD patients, we used a gene exclusively expressed in neurons, NSE, as the endogenous reference gene. NSE showed a high reliability over at least four orders of magnitude of input cDNA and similar PCR kinetics as SNCA. Additionally, an inter-run calibrator normalization and efficiency correction were applied. Despite these procedures, variability in the expression of SNCA could not be completely eliminated. In addition to the limited availability of human brain tissues, low population frequencies of certain genotypes of interest pose another problem for the power in genotype-phenotype association studies. Due to these general difficulties, our results are based on relatively low sample sizes and have to be seen as indicative only. Therefore, future replication studies will certainly be needed to confirm our findings in a higher number of individuals.
In our sample, SNCA protein levels in blood are significantly correlated with disease duration. This effect was not due to a higher age of patients with longer disease duration since age was neither correlated with disease duration nor with protein levels. When we tested for an effect of the disease status on -synuclein disease-normalized protein expression levels, we did not find a significant difference between sPD patients and controls, indicating that at point zero of the disease, -synuclein levels in the blood might not be different between individuals with beginning disease and healthy individuals. Therefore, disease duration should be considered in studies of -synuclein protein expression. Our findings of disease-duration-dependent increases in -synuclein protein levels in blood together with unchanged levels of disease-duration-normalized -synuclein protein levels between controls and sPD patients suggest that 1) either the increase in -synuclein protein levels in later disease stages is the consequence of non-SNCA related primary alterations in the course of sPD pathogenesis, i.e., mitochondrial and/or proteasomal damage (symptomatic rather than causal relationship); or 2) subgroups of sPD patients with a specific genetic make-up (i.e., risk haplotypes in the SNCA gene) might have altered -synuclein levels in certain brain regions or neuronal subpopulations that contribute directly to the pathogenic process but will be difficult to quantify in expression studies; or 3) blood mononuclear cells do not at all mirror the events in brain tissue. A possible effect of L-DOPA treatment on SNCA mRNA or protein levels in our blood cohort could be excluded.
Taken together, we provide, for the first time, in vivo evidence for a genotype-dependent expression regulation of -synuclein in blood (promoter repeat NACP-Rep1) and brain (rs356219 in the 3' region of SNCA). The understanding of regulatory mechanisms (i.e., genetic variations) of -synuclein expression levels, with a need for a tightly controlled balance of SNCA expression between protection and neurotoxicity, will be crucial for future therapeutic interventions aiming at a modulation of cellular -synuclein levels.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication June 29, 2007. Accepted for publication November 29, 2007.
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This article has been cited by other articles:
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  T. Gasser Genomic and proteomic biomarkers for Parkinson disease Neurology, February 17, 2009; 72(7_Supplement_2): S27 - S31. [Abstract] [Full Text] [PDF]
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 M. Westerlund, A. C. Belin, A. Anvret, A. Hakansson, H. Nissbrandt, C. Lind, O. Sydow, L. Olson, and D. Galter Cerebellar {alpha}-synuclein levels are decreased in Parkinson's disease and do not correlate with SNCA polymorphisms associated with disease in a Swedish material FASEB J, October 1, 2008; 22(10): 3509 - 3514. [Abstract] [Full Text] [PDF]
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