Interleukin-10 promoter polymorphisms in Chinese patients with Parkinson's disease

Interleukin-10 (IL-10), an important anti-inflammatory cytokine, may influence the risk for the development of onset of sparadic Parkinson's disease (PD) in the inflammatory process. In this study, two DNA polymorphisms at IL-10 gene promoter (-819 T/C and -592 A/C) were examined in 355 sporadic PD patients and 200 healthy controls in Han Chinese Population. For both polymorphisms, no significant difference in genotype or allele distribution was found between PD patients and the controls. For -819 T/C polymorphisms, there was significant difference in genotype distribution between EOPD (EOPD, <50 years of age) patients and each healthy-matched control subgroup (P=0.011), as well as between female PD patients and each healthy-matched control subgroup (P=0.024), For -592 A/C polymorphisms, there were no significant gender- and age-related differences in genotype distribution between PD patients and the controls subgroup. Results from our study revealed that the IL-10 promoter (-819 and -592) polymorphism is not a risk factor of sporadic Parkinson's disease, but the IL-10 promoter -819 polymorphism is a risk factor of EOPD and female PD patients in Han Chinese population.     

VEGF polymorphisms and serum VEGF levels in Parkinson's disease

In a previous study we were able to demonstrate that the Cutaneous Rabbit Effect (CRE) could be induced across fingertips using a form of the reduced rabbit paradigm and electrotactile stimuli. The CRE, as used here, is an illusory phenomenon where two stimuli are rapidly at a site and then a stimulus is presented to a nearby site. The perception of the second of the stimuli is not at its presented location but at a site between the first and last stimuli. In this experiment, though the overall population did perceive the mislocalized stimuli as the CRE would predict, some subjects were very infrequently observed to mislocalize stimuli due to the CRE or other effects. Here we further examine this phenomena, attempting to identify whether a subpopulation exists that rarely mislocalizes stimuli on their fingertips. To test for this subpopulation, we reexamined the collected data from the previously published experiment and other unpublished data relating to that study. By examining these data for rates of mislocalization utilizing our previous metric we identified that there is a perceptual subpopulation that very infrequently misidentifies the location of a fingertip stimulus.     

No association between polymorphism of serotonin transporter gene and depression in Parkinson's disease in Chinese

Depressive symptoms affect 40% to 50% of Parkinson's disease (PD) patients, and adversely impact their quality of life. The decrease of serotonin (5-HT) in the synaptic cleft is commonly considered as the cause of depression. The reuptake of 5-HT released into the synaptic cleft is mediated by the 5-HT transporter (5-HTT). Many studies have focused on the relationship between the 5-HTT-linked polymorphic region (5-HTTLPR) and depression. The present study is to investigate the association between the polymorphisms in the promoter of the 5-HTT gene (including 5-HTTLPR and rs25531), which determine either a higher or lower 5-HT uptake, and risk for depression of PD. Three hundred six idiopathic PD patients were recruited randomly from hospital clinic and the Center for Epidemiological Studies Depression Scale (CES-D) was used as the diagnosis or rating scale for depression. Polymerase Chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used and the patients’ genotypes were divided as L_A, L_G, S_A, and S_G. We found no evidence for an association between variants of 5-HTTLPR and rs25531 alleles, and depressive symptoms in Chinese PD patients.     

Parkinson's disease involves autophagy and abnormal distribution of cathepsin L

Accumulating evidences suggest that the related autophagy-lysosomal mechanism plays a critical role in many neurodegenerative disorders. In this study, we examined postmortem Parkinson's disease (PD) substantia nigra for evidence of cathepsin L by immunofluorescent staining, and found increased expression of cathepsin L in dopamine neurons of PD patients. We confirmed 6-OHDA induced nuclear translocation of cathepsin L in rat substantia nigral neurons as well. Furthermore, we observed autophagic vacuoles and lysosomes were accumulated in the 6-hydroxydopamine (6-OHDA) injured rat substantia nigra neurons with electron microscopy. Immunofluorescent staining showed that LC3 was enriched in dopamine neurons after 6-OHDA treatment. When pretreated with 3-methyladenine (3-MA), dopaminergic neurons were protected from cell death induced by 6-OHDA, associated with the suppression of LC3 and cathepsin L. Our results demonstrate that activation of autophagy and abnormal distribution of cathepsin L may be responsible for dopamine neuron death, involved in the pathogenic cascade event for the development of Parkinson's disease.     

Lack of association of polymorphism in miRNA-196a2 with Parkinson's disease risk in a Chinese population

MicroRNAs (miRNAs) are a new class of non-protein coding RNA molecules, which participate in diverse biological pathways. We hypothesized that miRNA-196a2 polymorphism is associated with the risk of Parkinson's disease (PD) in a Chinese population. In a case-control study of 549 PD patients and 736 control subjects frequency matched by age and gender, we genotyped the single-nucleotide polymorphism (SNP) rs11614913 (T>C) in miRNA-196a2, whose target mRNA was alpha-synuclein, and assessed its association with risk of PD by TaqMan Genotyping method. No association was found for the miR-196a2 rs11614913 CT/CC genotype (odds ratio (OR), 0.879, 95% confidence interval (CI), 0.681-1.135 for CT genotype; OR, 1.085, 95% CI, 0.793-1.484 for CC genotype) with risk of PD, compared with the TT genotype. These results suggest that SNP rs11614913 in miRNA-196a2 may not contribute to the susceptibility to PD.     

Mitochondrial translation initiation factor 3 gene polymorphism associated with Parkinson's disease

Mitochondrial dysfunction occurs early in late-onset sporadic Parkinson's disease (PD), but the mitochondrial protein network mediating PD pathogenesis is largely unknown. Mutations in the mitochondrial serine-threonine kinase PINK1 have recently been shown to cause the early-onset autosomal recessive PARK6 variant of PD. We have now tested a candidate interactor protein of PINK1, the mitochondrial translation initiation factor 3 (MTIF3) for involvement in PD pathogenesis. In two independent case-control collectives, the c.798C>T polymorphism of the MTIF3 gene showed allelic association with PD, with a maximal significance of p=0.0073. An altered function of variant MTIF3 may affect the availability of mitochondrial encoded proteins, lead to oxidative stress and create vulnerability for PD.     

Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease

Unlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD.     

BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups

Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here.     

Normal CAG and CCG repeats in the Huntington's disease genes of Parkinson's disease patients

The clinical features of Parkinson's disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington's disease. Therefore, the CAG and CCG repeats in the Huntington's disease gene were investigated in 45 Parkinson's disease patients and compared to 40 control individuals. All of the Parkinson's disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson's disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington's disease gene are not likely to contribute to the pathogenesis of Parkinson's disease. © 1995 Wiley-Liss, Inc.     

Visual hallucinations in Parkinson's disease are not influenced by polymorphisms of serotonin 5-HT2A receptor and transporter genes

Psychiatric disorders are common in Parkinson's disease (PD) and hallucinations are observed in nearly 40% of PD patients. The involvement of dopaminergic system in the pathogenesis of psychosis has been sustained by most of the authors even if several evidences indicate that multiple neurochemical substrates might underlie psychosis in PD. In PD there is an extensive loss of serotoninergic raphe neurons and serotonin dysfunction had been implicated in the pathogenesis of many psychiatric disorders such as depression, schizophrenia, and in psychosis of patients with Alzheimer disease. The association of a serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the 5-HT2A receptor T102C polymorphism with psychosis in a group of patients with PD was investigated. No significant differences in the distribution of allele and genotype frequencies of the 5-HTTLPR (p>0.01) and 5-HT2A T102C (p>0.05) were found between patients and controls as well as between the patients' subgroups without and with psychosis. These data might suggest that 5-HTTLPR and 5-HT2A polymorphisms are not major susceptibility factors of psychotic symptoms in PD patients.     

Favorable effects of VEGF gene transfer on a rat model of Parkinson disease using adeno-associated viral vectors

Vascular endothelial growth factor (VEGF) is a specific angiogenic peptide, which has been identified to play a critical role in neurodegeneration, and has beneficial effects on neurons. In this study, we investigated whether neurodegeneration in a rat model of Parkinson disease could be prevented by VEGF gene transfer mediated by adeno-associated virus (AAV) vectors. Our results demonstrated that a single injection of a VEGF-expressing AAV vector into striatum improved the rotational behavior of rat Parkinson disease models, and promoted the survival of dopaminergic neurons and fibers. Meanwhile, AAV-VEGF injection significantly increased the reactive astrocytes and the levels of glial cell line-derived neurotrophic factor in striatum, but did not induce extra angiogenesis and remarkable disorder of blood-brain barrier. We thus conclude that intrastriatal delivery of VEGF gene mediated by AAV has favorable effects on the dopaminergic neurons in a rat Parkinson disease model.     

Vitamin D receptor gene polymorphism and its association with Parkinson's disease in Chinese Han population

Vitamin D plays an important role in neurodegenerative disorders as a crucial neuro-immunomodulator, and accumulating data have provided evidence for that vitamin D receptor (VDR) gene is a candidate gene for susceptibility to Parkinson's disease (PD). In this study, we performed a case-control study to demonstrate whether the risk for the development of onset of sporadic PD might be influenced by VDR gene polymorphisms in a Chinese cohort. Two hundred and sixty PD patients and 282 matched-healthy controls were genotyped for two representative single nucleotide polymorphisms (SNPs) in VDR gene (FokI C/T and BsmI G/A) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis in. Results from our study revealed that FokI C allele carriers were likely to associate with an increased risk of PD (P = 0.004) as well as early-onset PD (EOPD) (P = 0.010). Moreover, the frequency of FokI C allele was significantly increased in PD group and late-onset PD (LOPD) group relative to the control groups respectively (P = 0.023 and P = 0.033, respectively). For BsmI polymorphisms, no significant difference in genotype or allele distribution was found between PD patients and the controls, as well as gender- and age-related differences between PD patients and the controls subgroup. This study demonstrated a possible association between the VDR FokI T/C polymorphism and PD, indicating that VDR polymorphisms may well change genetic susceptibility to sporadic PD in a Han Chinese population.     

Analysis of EIF4G1 in Parkinson's disease among Asians

Sequence analysis of all the exons of EIF4G1 in 96 Asian patients with Parkinson's disease (PD) did not reveal any pathogenic mutations. A novel coding variant (Pro693Ser) in exon 15 (position 2077) was detected in one PD patient but not in 539 control subjects. Analysis of a coding polymorphic variant (rs2178403) in 1330 subjects revealed similar frequency between control subjects (0.638) and PD patients (0.640). EIF4G1 is an uncommon cause of PD in our Asian cohort.     

Lower serum UA levels in Parkinson's disease patients in the Chinese population

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, and oxidative stress plays an important role in its pathogenesis. Uric acid (UA) is a product of purine metabolism and is a natural antioxidant that can relieve the oxidative stress that occurs in PD. Recent studies have indicated that the serum UA level are associated with a risk of PD and PD progression of motor symptoms and have proposed UA as a possible biomarker of the underlying pathophysiology of PD. In our study, we investigated the association between serum UA level and PD in a Chinese population. We found that the serum UA levels in PD patients were lower than the levels in control patients and were correlated with PD progression and duration in the Chinese population. These associations were observed in both genders, but hyperuricemia is more strongly associated with lower rates of PD among men compared to women and older people compared to younger people. Our results indicate that UA could be an important biomarker of PD and that the serum UA level could be a useful biomarker of PD diagnosis and disease progression.     

Cortical serotonin-S2 receptor binding abnormalities in patients with Alzheimer's disease: comparisons with Parkinson's disease

Reductions in the numbers of binding sites for the serotonergic S2-receptor antagonist, ketanserin, are, as previously reported, evident in Alzheimer's disease. New findings indicate that these sites are not affected in the cortex of patients with Parkinson's disease despite the presence of cognitive impairment. In contrast S1-receptor binding sites were reduced to a small but significant extent in both Alzheimer's and Parkinson's disease with cognitive deficit. The S2-receptor binding loss was not related to the cholinergic deficit (decreased choline acetyltransferase) common to both disorders nor to the presence of cortical senile plaques but did relate to the extent of cortical neurofibrillary tangle formation, evident in Alzheimer's but not generally in Parkinson's disease. These observations suggest that S2- but not S1-receptor binding abnormalities may reflect an important intrinsic cortical involvement specifically associated with the Alzheimer disease process.     

Akt signal transduction dysfunction in Parkinson's disease

Significant attention has been drawn to the potential role of defective PI3-kinase-Akt (PKB) signalling in Parkinson's disease (PD) neurodegeneration and to the possibility that activation of Akt may provide neuroprotection in PD. However, little knowledge exists on the integrity of the Akt system in PD. Results of the present study show diminished levels of both total and active phospho^Ser473-Akt in the brain in PD. This was evident by western blot analysis of midbrain fractions from PD compared to non-PD control brain, but more specifically by immunofluorescence microscopy of the substantia nigra pars compacta (SNpc). Here, double immunofluorescence microscopy found Akt and phospho^Ser473-Akt to be expressed at high levels in tyrosine hydroxylase (TH) immunopositive dopaminergic neurons in control human brain. Selective loss of these neurons was accompanied by a marked decrease of Akt and phospho^Ser473-Akt expression in the PD brain, however Akt and active phospho^Ser473-Akt are still evident in degenerating dopaminergic neurons in the disease. This suggests that it may be possible to target neuronal Akt in advanced PD. Converse to the marked loss of neuronal Akt in PD, increased Akt and phospho^Ser473-Akt levels were observed in small non-TH positive cells in PD SNpc, whose increased number and small nuclear size indicate they are glia. These findings implicate defective Akt as a putative signalling pathway linked to loss of dopaminergic neurons in PD.     

Triggering receptor expressed on myeloid cells 2 variants are rare in Parkinson's disease in a Han Chinese cohort

Recent studies have reported that a rare nonsynonymous variant rs75932628-T in the TREM2 gene is associated with increased risk of Alzheimer's disease and Parkinson's disease (PD) in European-descended populations. However, the association between rare TREM2 mutations and PD risk remains unknown in Chinese population. We directly sequenced exon2 of TREM2 in a cohort of 476 PD patients and 432 healthy controls from a Han Chinese population. Rs75932628-T (p.R47H) was found in 0.2% of PD cases (1/476) but in none of the controls (0/432, p = 1.000), with a minor allele frequency of 0.06% among the 908 subjects. Our findings suggest that variants in exon2 of TREM2 are extremely rare, and it is not a genetic risk factor for PD in the southern Han Chinese population.     

Quantitative plasma DNA analysis in Parkinson's disease

Parkinson disease (PD) is a neurodegenerative disease resulting from the loss of the dopaminergic neurons from the substantia nigra pars compacta (SNpc). It is characterized by bradykinesia, rigidity, resting tremor and/or postural instability. The diagnosis of PD is essentially clinical and there is no reliable biological marker to assess its progression. Recently, investigations have been performed on the potential use of circulating cell-free deoxyribonucleic acid (DNA) in the plasma for clinical diagnosis, prognosis and monitoring of human diseases. The aim of this work was to assess the role of free DNA as a biological marker of PD. Forty-two patients with PD (19 men, 23 women) and 20 healthy (7 men, 13 women) subjects were enrolled in this study. Mean ± SD plasma DNA concentration in PD patients and control subjects were, respectively, 16,487 ± 16,378 (range: 100–62,034) kilogenomes-equivalents/L and 37,975 ± 17,832 (range: 15,143–78,783) kilogenomes-equivalents/L. There was a significant difference between control and PD groups (p < 0.001). There was no correlation between plasma DNA levels and demographic or clinical parameters in PD patients. Free DNA does not seem to be a reliable marker of PD progression. Further research is warranted to confirm the present results to have some value as biomarkers in other neurodegenerative diseases.     

Serotonin transporter polymorphic region 5-HTTLPR modulates risk for Parkinson's disease

The association between the serotonin transporter gene (SLC6A4) polymorphisms, that is, 5-HTTLPR and rs25531, and Parkinson's disease (PD) remains to be further defined. We investigated this relationship in a Chinese cohort that comprised 504 PD patients and 504 controls. A total of 8 haplotypes and 14 genotypes of SLC6A4 were found in this population including a new variant of 5-HTTLPR, that is, 20_G. Our results presented that 5-HTTLPR was associated with an aggravated risk for PD (p = 0.005). The rs25531 alone is not associated with PD susceptibility. However, in a sub-classification based on the impact of 5-HTTLPR and rs25531 on 5-HTT expression, we observed a significant difference in 5-HTT expressing distribution in the cohort, accompanied by an apparently lower level of 5-HTT high expressing group, that is, the L_AL_A genotype, in the PD patients. Taken together, our data provide novel insight in support that the SLC6A4 polymorphisms, particularly 5-HTTLPR, and the serotonergic system are associated with PD etiology.     

The probable relation between Toxoplasma gondii and Parkinson's disease

Parkinson's disease (PD), a chronic progressive neurodegenerative disorder, has a mainly unknown multifactorial etiology. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration. Toxoplasmosis can be associated with various neuropsychiatric disorders. The most commonly affected central nervous system (CNS) region in toxoplasmosis is the cerebral hemisphere, followed by the basal ganglia, cerebellum and brain stem. Therefore, in this study, we aimed to investigate the possible association between Toxoplasma infection and PD by evaluating the serum anti-Toxoplasma gondii IgG antibodies. There were no difference between the socioeconomic status of the patients and control subjects and magnetic resonance images of the patients were normal. Serum anti-T. gondii IgG levels were measured using ELISA. There was no statistically significant differences among the patients and control subjects with respect to age (66.01 ± 12.14 years, 62.42 ± 5.93 years, p = 0.089; respectively) and gender. The sero-positivity rate for anti-T. gondii IgG antibodies in PD patients and control groups were 42.3 and 22.5%, respectively, and they were statistically significant (p = 0.006). These results suggest that Toxoplasma infection may be involved in the pathogenetic mechanisms of PD. If confirmed, this hypothesis would represent a valuable advancement in care of patients with Parkinson's disease.