Demographic data of patients with PD and control subjects analyzed for NACP-Rep1 region in
1. Introduction
Parkinson’s disease (PD) is a chronic and progressive neurological disorder characterized by resting tremor, rigidity, and bradykinesia, affecting at least 2% of individuals above the age of 65 years. Parkinson’s disease is a result of degeneration of the dopamine-producing neurons of the
It is now believed that the cause of PD, are both environmental and genetic factors. During the last two decades, there has been breakthrough progress in genetics of PD. It is known that genetic background of PD is in mutations a number of pathogenic genes PARK, e.g.
2. Mutations in PRKN , SPR and HTRA2 genes and polymorphism of NACP-Rep1 region of SNCA promoter in the patients with Parkinson’s disease
During the last two decades, there has been breakthrough progress in genetics of PD. Currently it is known that genetic background of PD is heterogeneous and mutations in a number of pathogenic genes (e.g.
Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established. Nevertheless, they are relatively rare types of PD and account for about 30% of the FPD and 3–5% of the SPD cases. Although 18 specific chromosomal locus (called
Summarizing, from the existing studies reported, it is not yet clear how common mutations in few genes, including:
2.1. Polymorphism of NACP-Rep1 region of SNCA promoter in the patients with Parkinson’s disease
The study by Chiba-Falek et al. (2006) has shown that the region NACP-Rep1 of
Region NACP-Rep1 contains dinucleotide repeats (TC)x(T)2(TC)y(TA)2(CA)z, which may vary both the number of repeats, and include substitutions of nucleotides. However, it has been proven, that a change in the length of the NACP-Rep1 region more than substitutions, affects the regulation of the expression of ASN (Fuchs et al., 2008; Mellick et al., 2005; Tan et al., 2003). As the most common in humans it has been described five alleles of NACP-Rep1 of the
Functional analysis on the two most common NACP-Rep1 alleles +1 and +2 suggested that the +2 allele is associated with an up-regulation of
Nerveless, although protective effect of allele +1 rather not currently subject to discussion, but for alleles 0, +2 and +3 it has been suggested both no impact, as well as increasing the risk of PD, and even sometimes the protective action (Maraganore et al., 2006; Spadafora et al., 2003; Tan et al., 2000; Trotta et al., 2012). The following studies by Tan et al. (2000) and Myhre et al. (2008) observed a higher frequency of the +3 allele in PD cases compared with healthy controls while in the study by both Tan et al. (2003) and Spadafora et al. (2003) no significant differences of the various genotypes between PD and controls were found in population of Singapore and Italy. However, the study in Italy population, have also shown evidence of association for allele +2 on NACP-Rep1 (Trotta et al., 2012). In 2006, a meta-analysis of 11 study populations provided strong evidence that the 263bp allele was more frequent in PD cases increasing risk of this disease while the 261bp allele did not differ between PD cases and unaffected controls but the authors suggested, that the lack of association of the +2 allele in the meta-analysis could be due to the large fluctuation in its frequencies observed in the analyzed populations (Maraganore et al., 2006). Therefore the aim of the study was analysis of NACP-Rep1 region in PD patients and in controls in Polish population.
2.1.1. Patients
The studies were conducted on 90 patients with PD [SPD patients, 10 with early onset of PD, EOPD, and 80 with late onset of PD, LOPD patients), including 42 women and 47 men aging 34-82 years. Control group included 113 individuals, 79 women and 34 men, 39-83 years of age. Demographic data of all groups summarized in Table 1.
Patients with PD were diagnosed using the criteria of UK Parkinson’s Disease Society Brain Bank (Litvan et al., 2003), however stage of disease according to the scale of Hoehn and Yahr (Hoehn & Yahr, 1967).
None of the control subjects had verifiable symptoms of dementia or any other neurological disorders. All subjects had negative family history of PD. All patients were recruited from the Neurology Clinic of Chair and Department of Neurology, University of Medical Sciences, Poznan in Poland. Only Caucasian, Polish subjects were included in this study. A Local Ethical Committee approved the study and the written consent of all patients or their caregivers was obtained.
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113 | 90 |
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39-83 | 34-82 |
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55.5±9.5 | 61.9±10.1 |
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79/34 | 42/47 |
2.1.2. Genetic investigations
Moreover, random duplicate samples (10%) were genotyped for all assays for quality control with 100% reproducibility.
2.1.3. Results
Screening for mutation c.88 G>C of
Using PCR amplification and capillary electrophoresis five previously described polymorphic alleles of NACP-Rep1 region in
The frequency of +1/+1 genotype was almost fourfold higher in control group than in PD patients (p<0.001) whereas the frequency of the genotype +1/+2 was similar in both groups (Table 3). Comparisons of +2/+2 genotype frequencies between PD patients and control group revealed no significant differences but the frequency of this genotype was almost twofold higher in PD patients as compared to controls (p=0.056). It has been also detected, that the frequency of +2/+3 was significantly higher in PD patients compared to controls and was almost threefold higher in PD patients (p<0.05). Moreover, genotype +1/+3 has been detected only in one PD patient while genotype -1/+1 occurred only in controls (Table 3).
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|
1% | 0% |
|
5% | 6% |
|
53% | 33%*** |
|
40% | 54%** |
|
2% | 7%* |
|
226 | 180 |
|
|
|
|
2% | 0% |
|
7% | 7% |
|
3% | 4% |
|
23% | 6%*** |
|
50% | 47% |
|
0% | 1% |
|
12% | 22% |
|
4% | 13%* |
Total subjects number |
113 | 90 |
Logistic regression analysis have shown, that PD risk (as measured by OR, Table 4) has been reduced in presence of allele +1 and reduces with increasing dose of +1 allele. Moreover, OR pointed to the association the presence of allele +2 with increased risk of PD manifestation in dose dependent manner. Influence of the presence of allele +3 of the increase PD risk has been detected only in heterozygous variant. Genotype +3/+3 have not been detected in any person in both control and PD patient group.
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- | >0,05 | - | >0.05 | - | >0.05 (F) |
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- | >0,05 | - | >0.05 | - | >0.05 (C) |
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0.406 (0.210-0.785)** |
|
0.107 (0.035-0.322)*** |
|
0.342*** |
|
|
2.719 (1.292-5.719)** |
|
4.615 (1.774-12.009)** |
|
2.163*** |
|
|
4.601 (1.445-14.647)** |
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- | >0.05 | 4.601** |
|
Our results similarly to studies in the European, Australian and American populations indicated that, the presence of genotype +1/+1 may reduce PD risk while another study failed to replicate the finding in population of Italy (Fuchs et al., 2008; Maraganore et al., 2006; Mellick et al., 2005; Polrolniczak et al., 2012; Spadafora et al., 2003; Tan et al., 2003; Trotta et al., 2012). It is suggested, that reduction of PD risk by genotype +1/+1 may be related with decreasing ASN expression (Chiba-Falek et al., 2006; Fuchs et al., 2008). In the study in Polish population it has been also observed, in PD patient with genotype +1/+1 tendency to slower progression of the disease and better response to pharmacotherapy at using low doses of the L-dopa treatment compared the other genotypes of NACP-Rep1 (Polrolniczak et al., 2012). It seems, that in PD patients with genotype +1/+1 reduced ASN level, due to reduce ASN aggregation and maintenance of dopamine homeostasis in the central nervous system (CNS) probably leads to milder course of disease compared to patients with other genotypes of NACP-Rep1 (Maguire-Zeiss et al., 2005).
Although the study in Singapore and Italian populations shown no association for alleles +2 and +3 with PD our results confirming the study in populations: German, Italian, Japanese, and multipopulation research detected higher frequency of those alleles in PD patients compared with controls and indicated association of genotypes +2/+2 and +2/+3 with increased risk of PD in Polish population (Maraganore et al., 2006; Mellick et al., 2005; Polrolniczak et al., 2012; Spadafora et al., 2003; Tan et al., 2003; Trotta et al., 2012). It is believed that the influence of genotype +2/+2 and +2/+3 on the risk of PD most likely may be associated with over-expression of ASN, leading to increased aggregation of ASN and the severity of the neurotoxic effect (Chiba-Falek et al., 2006; Cronin et al., 2009; Fuchs et al., 2008). Furthermore in our study in patients with genotypes +2/+2 and +2/+3 we observed tendency to faster progression of the disease but no association with response to therapy (Polrolniczak et al., 2012). This observations seems corresponding with the results of the study by Ritz et al. (2012) shoved that risk of faster decline of motor function was increased four-fold in carriers of the +3 allele of NACP-Rep1 promoter variant. Moreover, the study by Kay et al. (2008) have indicated a trend of decreasing onset age with increasing allele size while the other study have shown, that age at onset of carriers of at least one allele +2 was earlier compared to noncarriers (Hadjigeorgiou et al., 2006).
However, in contrast to the results of Kay et al. (2008) in Polish population it has not indicated any association of allele 0 with risk of PD, however presence of this genetic variant was correlated in Spearman correlation test (p=0,019; r=-0,507) with decrease in stage of disease in patients suffering for PD over 10 years compared patients with the other genotypes of NACP-Rep1 (Polrolniczak et al., 2012).
It seems that examination of genotypes of region NACP-Rep1 of
2.2. Mutations in PRKN in the patients with Parkinson’s disease
Mutations of
Furthermore, it has been shown that mutations in the gene
It is suggested, that mutations in
The study by Abbas et al. (1999), point mutations of
The observation, that mutations in the
The aim of the study was to estimate the frequency of
2.2.1. Patients
According to the inclusion and exclusion criteria a total of 199 subjects were included in this study: 87 SPD patients (10 EOPD patients, and 77 sporadic LOPD patients), including 41 women and 45 men aging 34-82 years. Control group included 112 individuals, 78 women and 34 men, 39-83 years of age. Demographic data of all groups summarized in Table 5. Patients with PD were diagnosed using the criteria of UK Parkinson’s Disease Society Brain Bank (Litvan et al., 2003), however stage of disease according to the scale of Hoehn and Yahr (Hoehn & Yahr, 1967). None of the control subjects had verifiable symptoms of dementia or any other neurological disorders. All subjects had negative family history of PD. All patients were recruited from the Neurology Clinic of Chair and Department of Neurology, University of Medical Sciences, Poznan in Poland. Only Caucasian, Polish subjects were included in the study. A Local Ethical Committee approved the study and the written consent of all patients or their caregivers was obtained.
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112 | 87 |
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39-83 | 34-82 |
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55.6±9.5 | 61.4±9.9 |
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78/34 | 41/45 |
2.2.2. Genetic investigations
Moreover, random duplicate samples (10%) were genotyped for all assays for quality control with 100% reproducibility.
2.2.3. Results
Analysis of deletions of exons 2 and 4
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8% | 31%*** | 6.059 | 2.188-11.207 | <0.001 (C) |
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112 | 87 | - | - | - |
In exon 4 of
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1% | 0% | 0% | 5% | 2% |
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7%* | 2% | 1% | 18%** | 11%** |
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8.000 | - | - | 3.926 | 6.938 |
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0.945-67.712 | - | - | 1.436-10.735 | 1.480-32.528 |
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<0.05 (F) | >0.05 (F) | >0.05 (F) | <0.01 (C) | <0.01 (C) |
Additionally in 5% PD patients it has been detected more than one mutation in
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c.823 C>T , c.1180 G>A | 1% |
c.500 G>A, c.520 C>T | 1% |
c.930 G>C, c.1180 G>A | 2% |
c.500 G>A, c.930 G>C, c.1180 G>A | 1% |
It is suggested, that single or multiple exon deletions and duplications occur with a frequency of 15.8% and account for about 50% of all mutations of
However, point mutations in
Furthermore there is no question that Parkin-associated parkinsonism is recessive; that is, both alleles are mutant, but despite previous reports whether a heterozygous mutation can cause or increase the risk for PD remains an issue of debate (Farrer et al., 2001; Klein et al., 2000; Lucking et al., 2001; Maruyama et al., 2000).
In the German population the frequency of
Moreover, we showed, that in the Polish population the most frequently were polymorphisms c.500 G>A, c.1180 G>A and c.930 G>C of
It is suggested, that haploinsufficiency may be considered as a reduction of normal gene expression accompanied by a loss of normal protein activity. Moreover, a lot of reports indicate to the existence of a second, undetected mutation in these patients, perhaps in the promoter or intronic regions (Giasson & Lee, 2001).
Our results, also suggests that the presence more than one heterozygous mutation in the
Finally, it seems that clinically, PD patients with
It seems, that point mutation in
2.3. Mutations in HTRA2 and SPR in the patients with Parkinson’s disease
It seems that presence of mutation in the other genes involved in the pathogenesis of PD like
Locus of
2.3.1. Patients
The studies were conducted on 89 patients with PD (10 EOPD patients, and 79 sporadic LOPD patients), including 41 women and 47 men aging 34-82 years. Control group included 113 individuals, 79 women and 34 men, 39-83 years of age. Demographic data of all groups summarized in Table 9.
Patients with PD were diagnosed using the criteria of UK Parkinson’s Disease Society Brain Bank (Litvan et al., 2003), however stage of disease according to the scale of Hoehn and Yahr (Hoehn & Yahr, 1967).
None of the control subjects had verifiable symptoms of dementia or any other neurological disorders. All subjects had negative family history of PD. All patients were recruited from the Neurology Clinic of Chair and Department of Neurology, University of Medical Sciences, Poznan in Poland. Only Caucasian, Polish subjects were included in the study. A Local Ethical Committee approved the study and the written consent of all patients or their caregivers was obtained.
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113 | 89 |
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39-83 | 34-82 |
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55.5±9.5 | 62.0±10.1 |
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79/34 | 41/47 |
2.3.2. Genetic investigations
2.3.3. Results
In Polish population the presence of
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0% | 0% | 0% | 0% |
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1% | 2% | 0% | 3% |
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- | - | - | 9.080 |
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- | - | - | - |
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>0.05 (F) | >0.05 (F) | >0.05 (F) | =0.05 (F) |
In 213 codon of
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2% | 0% |
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4% | 0% |
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- | - |
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- | - |
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>0.05 (F) | >0.05 (F) |
In PD patients with substitutions in
Moreover, it seems that mutation c.637 T>A, because of localization, probably may affect phosphorylation of SR and thereby its activity and finally regulate biosynthesis of DA and serotonin (5-HT). However, analysis of expression and functional testing are necessary to explain importance and role of this mutation. Nevertheless, what is important, in our study c.637 T>A
2.4. Coexistence of mutations in more than one gene (SNCA, PRKN , HTRA2 and SPR) in the patients with Parkinson’s disease
Our study indicated, that in PD patients as well as in controls in the Polish population,
Furthermore, in the patients with PD we demonstrated coexistence of point mutations in
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25 | PD patient | c.500 G>A | - | c.637 T>A |
114 | PD patient | c.930 G>C | c.1195 G>A | - |
202 | PD patient | c.930 G>C | c.421 G>T | - |
18 | Control | c.930 G>C | - | c.637 T>A |
3. Role of alpha-synuclein in pathogenesis of Parkinson’s disease
Alpha-synuclein is a protein composed of 140 amino acids and is a part of family of proteins with the β- and γ-synuclein (Clayton & George, 1998). For many years, the structure of ASN was determined as the,,not-folded" chain of amino acids, taking the helical form only in conjunction with the lipids of cell membranes. It was thought that the ASN is a monomer form but the recent studies have shown that under physiological conditions ASN largely takes the form of tetramers, and may take the helical form without connection to the lipid membrane (Bartels et al., 2011).
Immunohistochemical studies have shown that in the cells, there is essentially ASN bonded to both the nuclear membrane, and in the synaptic vesicles (Totterdel & Meredith, 2005). To a lesser extent, ASN occurs in the free form in the cytoplasm.
Functions of ASN are not fully understood, however, due to cellular location of this protein it is suggested, that function of ASN may be related with the synaptic transport (Alim et al., 2002). There are also reports indicating that ASN participate in the process of differentiation and survival of the dopaminergic neuron progenitor cells of the mouse and human (Michell et al., 2007; Schneider et al., 2007).
Under pathological conditions ASN may change the structure and take the form of beta harmonica, what may lead to aggregation of ASN and formation of soluble oligomers, and then the insoluble filaments and deposits in the nerve cells (Bodles et al., 2001). As it have been shown, ASN is one of the main components of Lewy’s bodies (LB), pathology, round or polymorphonuclear cellular inclusions in the cytoplasm of nerve cells. Moreover, it is suggested, that the formation of insoluble deposits of ASN and the aggregation process may give rise to the formation of LB (Halliday et al., 2006).
It is obvious that the process of aggregation of the ASN is a negative phenomenon for neural cells not only because of the high toxicity of the resulting aggregates, but also because of the ASN physiological function disorders caused by the reduction of bioavailability of this protein (Conway et al., 2000). It has been shown, that in PD, the process of ASN aggregation may be modulated by a number factors (Fig. 2) [Haggerty et al., 2011; Li et al., 2008; Ren et al., 2009; Sherer et al., 2002].
3.1. Alpha-synuclein concentration in Parkinson’s disease
It has been shown that aggregation of the ASN may be caused among others by multiplication of
The aim of the study was to estimate the concentration of ASN in plasma of patients with PD and in control group.
3.1.1. Patients
The studies were conducted on 32 patients with PD, including 18 women and 14 men aging 35-82 years. Control group included 24 individuals, 20 women and 4 men, 40-69 years of age. Demographic data of all groups summarized in Table 13.
Patients with PD were diagnosed using the criteria of UK Parkinson’s Disease Society Brain Bank (Litvan et al., 2003), however stage of disease according to the scale of Hoehn and Yahr (Hoehn & Yahr, 1967). None of the control subjects had verifiable symptoms of dementia or any other neurological disorders.
All patients were recruited from the Neurology Clinic of Chair and Department of Neurology, University of Medical Sciences, Poznan in Poland. Only Caucasian, Polish subjects were included in the study.
A Local Ethical Committee approved the study and the written consent of all patients or their caregivers was obtained.
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24 | 32 |
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40-69 | 35-82 |
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55.3±6.8 | 62.5±10.5 |
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20/4 | 18/14 |
3.1.2. Analysis of ASN concentrations
3.1.3. Results
Detectable concentrations of ASN have been detected in higher percentage of controls than in PD patients. However, in patients with PD has been shown higher concentration of ASN (Table 14).
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Detectable concentrations of ASN, n [%] | 4 [17%] | 4 [12%] |
ASN concentrations [pg/ml] | [68.19-645.57] | [55.2-1294.9] |
In PD patients, the highest concentrations of ASN were present in two first stages of disease progress (Hoehn and Yahr scale) [Table 15] and in the first ten years of the disease (Table 16).
1 | [55.2] |
2 | [60.94-1294.9] |
3 | - |
|
|
< 5 years | [55.2-293.67] |
5-10 years | [1294.9] |
>10 years | - |
In this study and Bialek et al. (2011) have been shown higher concentration of plasma ASN level in PD patients as compared to controls. However, it seems that aggregation of the ASN in the nerve cells may reduce ASN ability to pass through the blood-brain barrier, which in turn may result in significantly reduced levels of this protein in the peripheral blood. Moreover, a high concentration of ASN has been detected only in the initial period of PD (in two first stages of PD progress in Hoehn and Yahr scale, and in the first ten years of the disease), probably even before the accumulation of deposits in the form of LB in the brain of PD patients. However, in the study by Pchelina et al. (2011) the level of ASN was significantly lower in patients with
4. Role of Parkin in pathogenesis of Parkinson’s disease
Parkin is a cytoplasmic protein which plays a vital role in the proper functioning of the mitochondria and functions as an E3 ligase ubiquitin stimulating protein binding (directed to degradation in the proteasome) with ubiquitin, consequently preventing the cell apoptosis (Zhang et al., 2000). Ubiquitination is a vital cellular quality control mechanism that prevents accumulation of misfolded and damaged proteins in the cell. It is thought that substrates of Parkin include among others synphilin-1, ASN, CDC-rel1, cyclin E, p38 tRNA synthase, Pael-R and synaptotagmin XI. It has been shown in the study by Zhang et al, [2000] Parkin is also responsible for their own ubiquitination and degradation in the proteasome.
Recent studies have shown that Parkin may play a role in decision-making, choosing between two systems of degradation: the proteasome activity (through its ability to promote ubiquitination K48 associated with the proteasome) and macroautophagy (through K63 ubiquitination related to cell signaling and the formation of LB) [Henn et al., 2007; Lim et al., 2006].
4.1. Parkin concentration in Parkinson’s disease
The aim of the study was to estimate the concentration of Parkin in plasma of patients with PD and in control group.
Patients (see point 3.1.1.)
Analysis of Parkin concentrations
4.1.1. Results
Detectable concentrations of Parkin have been detected in similar percentage of controls and PD patients. However, in patients with PD has been shown lower concentration of Parkin (Table 17).
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Detectable concentrations of Parkin, n [%] | 5 [21%] | 7 [22%] |
Parkin concentrations [ng/ml] | [0.036-4.436] | [0.076-2.123] |
In PD patients, the highest concentration of Parkin occurred in 2 stage of disease progress with tendency to reduce the concentration in the 3 stage of the disease (Hoehn and Yahr scale) [Table 18] and in the first ten years of the disease (Table 19).
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|
1 | - |
2 | [0.158-2.123] |
3 | [0.076-0.409] |
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< 5 years | [0.549-2.123 ] |
5-10 years | [0.158-2.054] |
>10 years | [0.076] mutation in 11 exon of |
It is known that dysfunction of Parkin may lead to manifestation of PD in several mechanism including mitochondrial and ubiquitination disturbances. It also seems that expression and cellular level of Parkin may be essential factor for proper function of this protein. However, the presence of Parkin protein has been demonstrated in human serum using Western blotting, there is few analysis of the level of this protein in the blood of PD patients (Dorszewska et al., 2012; Kasap et al., 2009). In the study by Dorszewska et al. (2012) has been detected lower plasma Parkin concentration in PD patients than in controls. Moreover, increased levels of the Parkin have been detected in PD patients in the early stages of PD (Hoehn and Yahr scale) and decreasing with the progress and duration of this disease. It seems that in the early stages of PD development may occur to increase of Parkin expression through the ongoing degenerative process and to the accumulation of pathological proteins-Parkin substrates. However, as the disease progresses, probably, resources of the Parkin running out and occurs weaken its neuroprotective function.
5. Relationship between alpha-synuclein and Parkin levels in Parkinson’s disease
In 2001, Shimura et al. first described the presence in the human brain complex containing Parkin with the glycosylated form of the ASN (alpha-SP22), thus indicating the involvement of Parkin in ASN degradation in ubiquitin-proteasome system [Shimura et al., 2001; Chung et al., 2004]. It has been also shown that dysfunction of the Parkin can lead to ineffective elimination of ASN and the aggregation of this protein [Haass & Kahle, 2001]. In addition, according to the reports, the Parkin may also interact with the dopamine and indirectly influence the aggregation of the ASN in the nerve cell (Oyama et al., 2010). Therefore, it seems that the levels of these two proteins may be related and dependent on each other.
Patients (see point 3.1.1.)
Analysis of ASN (see point 3.1.2.), and Parkin (see point 4.1.2.) concentrations
5.1. Results
In patients with PD detectable levels of Parkin occurred in a nearly two-fold higher incidence than the ASN (Tables 14, 17).
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|
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ASN concentration [pg/ml] | [68.19-645.57] | [55.2-1294.9] |
Parkin concentration [pg/ml] | [36.0-4436.0] | [76.0-2123.0] |
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|
|
1 | [55.2] | - |
2 | [60.94-1294.9] | [158.0-2123.0] |
3 | - | [76.0-409.0] |
< 5 years | [55.2-293.67] | [549.0-2123.0 ] |
5-10 years | [1294.9] | [158.0-2054.0] |
>10 years | - | [76.0] mutation in 11 exon of |
In this study and studies by Bialek et al. (2011) and Dorszewska et al. (2012) have been shown, that in PD patients increased level of ASN was associated with the decreased level of Parkin in contrast to control group (Tables 20-22). Independently for the analyzed group, the highest levels of ASN have been observed in the subjects who had very low Parkin levels. It suggested that low concentration of Parkin may contribute to increased ASN level in the nerve cells and combined with over-expression of ASN intensify or accelerate neurodegenerative process. Moreover, it has been also shown that configuration: increased plasma level of ASN and decreased of Parkin was associated with earlier onset of this disease.
6. Mutations in PARK (PRKN, SPR, HTRA2, SNCA ) genes and ASN and Parkin concentrations in Parkinson’s disease
Our study on Polish population shown that in PD patients
It seems that analysis of these pathological proteins with PARK gene mutations may be useful in the diagnostic and monitoring of the PD progress in the future.
7. Conclusion
In Polish population, in
Analysis of the variations of PARK gene as well as plasma levels of ASN and Parkin may consist an additional diagnostic factor for PD.
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