共查询到20条相似文献,搜索用时 15 毫秒
1.
Claudia Funke Juergen Tomiuk Olaf Riess Daniela Berg Anne S. Soehn 《Journal of neural transmission (Vienna, Austria : 1996)》2009,116(7):853-859
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic inclusions
(Lewy bodies). Iron, which is elevated in the substantia nigra (SN) of PD patients, seems to be of pivotal importance, because
of its capacity to enhance the amplification of reactive-oxygen species. Therefore, it is tempting that the iron-releasing
key enzyme in heme catabolism, heme oxygenase-1 (HO-1), may represent a candidate for a genetic susceptibility to PD. In the current study, we examined a (GT)n fragment length
polymorphism in the promoter region, as well as three coding SNPs in the HO-1 gene in order to assess if certain genotypes are associated with PD. Furthermore, peripheral blood expression levels of HO-1 in PD patients and healthy probands were compared. However, our analyses did not reveal a significant association of these
genetic markers in the HO-1 gene with an increased susceptibility to PD. 相似文献
2.
Over the last decades, increasing knowledge about the genetic architecture of Parkinson’s disease has provided novel insights
into the pathogenesis of the disorder, generating hypotheses for further research. Characterizing the role of SNCA, encoding the α-synuclein protein, has been a particularly important aspect of this development. The identification of SNCA as the first gene implicated in monogenic parkinsonism led to the recognition of α-synuclein as a key protein in the pathogenesis
and a major component of pathological hallmark lesions. An association between common variants in SNCA and risk of sporadic Parkinson’s disease has been established through numerous studies. We review our current understanding
of SNCA variability contributing to Parkinson’s disease, highlighting the characterization of functionally relevant susceptibility
alleles as a major future challenge. We argue that new strategies will be needed to pinpoint the variants that are ultimately
responsible for the signals detected in association studies, where targeted resequencing may represent an attractive initial
approach. 相似文献
3.
Keyser RJ Oppon E Carr JA Bardien S 《Journal of neural transmission (Vienna, Austria : 1996)》2011,118(6):889-897
4.
Oxidative stress has been proposed to be an important factor in the pathogenesis of Alzheimer’s disease (AD) and contributed
to β-amyloid (Aβ) generation. Interaction between oxidative stress and neuro-inflammation leads to Aβ generation. AD is associated with an
increase in blood–brain barrier (BBB) permeability due to tight junction involvement. Oxidative stress decreases the expression
of low-density lipoprotein receptor-related protein 1 and up-regulates receptor for advanced glycation end products in BBB
and increases the BBB permeability, which could potentially lead to increased deposition of Aβ within AD brain. Apoptosis takes place in the pathogenesis of AD, and oxidative stress contributes to apoptosis through both
extrinsic pathway and intrinsic pathway. Oxidative stress-induced apoptosis may be a potential factor to Aβ generation. Aβ generation requires two sequential cleavages of APP, with the two proteolytic enzymes: β-secretase and γ-secretase. Oxidative damage up-regulates Aβ via inducing activity of β- and γ-secretases. In this review, we will focus on the mechanism and pathway that oxidative stress contributes to Aβ generation. 相似文献
5.
Qicong Chen Biyu Liang Ziyou Wang Xiaoguang Cheng Yifeng Huang Yong Liu Zunnan Huang 《Neurological sciences》2016,37(8):1209-1220
We preformed this meta-analysis to investigate the influence of ABCA1 (ATP-binding cassette sub-family A member 1) rs2422493 (C-477T), rs1800977 (C-14T), rs2066718 (V771M), and PTGS2 (Prostaglandin-endoperoxide synthase 2) rs20417 (G-765C) polymorphisms on the risk of Alzheimer’s disease (AD). Seventeen eligible case–control studies were acquired from PubMed, Embase, Alzgene, Chinese National Knowledge Infrastructure and Wanfang databases. The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CI) were calculated to evaluate the association under five genetic models. Combined data indicated that ABCA1 rs2422493 polymorphism was statistically significant associated with increasing AD risk in three genetic models (allelic T vs C: OR = 1.12, 95 % CI: 1.01–1.24; homozygous TT vs CC: OR = 1.26, 95 % CI: 1.03–1.55; and recessive TT vs TC + CC: OR = 1.33, 95 % CI: 1.12–1.58) while no association was found between two other ABCA1 polymorphisms and AD susceptibility. Nevertheless, a further risk-stratification analysis showed that ApoE-ε4 carriers with any ABCA1 polymorphism suffered a much higher probability to be AD patients. Meanwhile, PTGS2 rs20417 polymorphism was linked to decreasing AD risk with a P < 0.0001 in five genetic models (e.g., allelic C vs G: OR = 0.59, 95 % CI: 0.50–0.70; homozygous CC vs GG: OR = 0.31, 95 % CI: 0.18–0.52; and heterozygous CG vs GG: OR = 0.64, 95 % CI: 0.52–0.78). In summary, our meta-analysis results showed that ABCA1 rs2422493 polymorphism was a risk factor for AD while PTGS2 rs20417 variant showed a protective effect on AD risk. In addition, ABCA1 rs2066718 and rs1800977 polymorphisms might not contribute to AD susceptibility in general population, but they should play a role on AD development when interacted with ApoE-ε4. 相似文献
6.
Neda Shahmohammadibeni Simin Rahimi-Aliabadi Javad Jamshidi Babak Emamalizadeh Hossein Ali Shahmohammadibeni Alireza Zare Bidoki Haleh Akhavan-Niaki Hajar Eftekhari Shokoufeh Abdollahi Mahmoud Shekari Khaniani Mahnaz Shahmohammadibeni Atena Fazeli Marzieh Motallebi Shaghayegh Taghavi Azadeh Ahmadifard Amir Ehtesham Shafiei Zarneh Monavvar Andarva Tahereh Dadkhah Ehteram Khademi Elham Alehabib Mahnoosh Rahimi Abbas Tafakhori Minoo Atakhorrami Hossein Darvish 《Neurological sciences》2016,37(5):731-736
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. Both genetic and environmental factors are involved in the etiology of the disease. Many studies have revealed the susceptibility genes and variations for PD which need further confirmation. Here we evaluated the association of variations in SNCA, HUSEYO and CSMD1 genes with PD. A case–control study was conducted with 489 PD patients and 489 healthy controls. DNA was extracted from peripheral blood of all subjects and rs356220 and rs11931074 in SNCA, rs2338971 in HUSEYO and rs12681349 in CSMD1 were genotyped using PCR–RFLP method. The genotypes and allele frequencies were significantly different between case and control groups for rs356220, rs11931074 and rs2338971 but not for rs12681349. We provided further evidence that rs356220 is associated with increased risk of PD supporting previous studies in Caucasian-based and Japanese populations. The association of rs11931074 with decreased risk of PD was also significant. This study revealed the first evidence of the association of rs2338971 with increased risk of PD in the Iranian population. Nevertheless, these findings need further validation via more replication studies. 相似文献
7.
Lamei Yuan Zhi Song Xiong Deng Zhijian Yang Yan Yang Yi Guo Hongwei Lu Hao Deng 《神经科学通报》2017,33(5):510-514
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and has an elusive etiology. It is likely multifactorial, and genetic defects contribute to its pathogenesis. At least 25 genetic loci and 20 monogenic genes have been identified in monogenic PD. Recessive F-box protein 7 gene (FBXO7) mutations reportedly cause hereditary parkinsonism. To explore the roles of four paralogs (FBXO2, FBXO6, FBXO12, and FBXO41) in PD development, their variants (rs9614, rs28924120, rs6442117, and rs61733550, respectively) were analyzed in 502 Han Chinese patients with PD and 556 age, gender, and ethnicity-matched normal participants in mainland China. Statistically significant differences in genotypic and allelic frequencies were detected only in the FBXO2 variant rs9614 (P = 0.001 and 0.023, respectively; odds ratio 0.819, 95% confidence interval 0.690–0.973) between patients and controls. These results suggest that the FBXO2 variant rs9614 C allele may decrease the PD risk in mainland Han Chinese and may be a biomarker for PD. 相似文献
8.
The distribution of cerebrovascular amyloid in Alzheimer’s disease varies with <Emphasis Type="Italic">ApoE</Emphasis> genotype 总被引:1,自引:0,他引:1
Trembath D Ervin JF Broom L Szymanski M Welsh-Bohmer K Pieper C Hulette CM 《Acta neuropathologica》2007,113(1):23-31
We performed a comparative study to assess cerebral amyloid angiopathy and ApoE genotype in cases of Alzheimer’s disease (AD). Ten ApoE 3,3 and ten ApoE 4,4 AD brains, as well as ten normal control brains, were selected after matching for age, sex, and duration of disease. Sections of middle frontal and inferior parietal cortex including white matter sections were stained with an antibody against amyloid beta (Aβ), and extensive analysis of arteriolar Aβ deposition was performed using digital image analysis. Quantification of the staining revealed a larger cross-section of arteriolar walls occupied by Aβ in ApoE 4,4 and ApoE 3,3 AD subjects compared to controls. Our results show Aβ deposition in gray matter and white matter arterioles was predominantly found in ApoE 4,4 brains and, overall, Aβ deposition was greatest in these cases. This observation implies that there is greater vascular amyloid deposition (particularly in the white matter arterioles) in ApoE 4,4 AD individuals compared to ApoE 3,3 AD. These observations may give insight into the etiology behind the increased risk for AD associated with the ApoE-ε4 allele and the pathogenesis of vascular Aβ deposition.This study was supported by the National Institutes of Health NIA P50 AG05128 and P30 AG028377. 相似文献
9.
Guiyou Liu Tao Wang Rui Tian Yang Hu Zhifa Han Pingping Wang Wenyang Zhou Peng Ren Jian Zong Shuilin Jin Qinghua Jiang 《Journal of molecular neuroscience : MN》2018,66(1):37-43
Genetic association studies have identified significant association between the GAB2 rs2373115 variant and Alzheimer’s disease (AD). However, it is unknown whether rs2373115 affects the regulation of nearby genes. Here, we evaluate the potential effect of rs2373115 on gene expression using multiple eQTL (expression quantitative trait loci) datasets from human brain tissues from the Mayo Clinic brain expression genome-wide association study (eGWAS), the UK Brain Expression Consortium (UKBEC), the Genotype-Tissue Expression (GTEx) project, and the Brain xQTL Serve. Our findings indicate that the rs2373115 C allele is associated with increased NARS2 expression, and both reduced and increased GAB2 expression in human tissues. Using a large-scale AD case-control expression dataset, we found increased GAB2 expression and reduced NARS2 expression in AD cases compared with controls. We believe that our findings provide important information regarding the rs2373115 variant and expression of nearby genes with respect to AD risk. 相似文献
10.
11.
Doraiswamy PM 《Current neurology and neuroscience reports》2003,3(5):373-378
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with an unknown etiology. Pathologic processes implicated
in AD include β-amyloid-induced synaptic failure; tau hyperphosphorylation; inflammation; oxidative stress; abnormal neurotransmission
involving acetylcholine, glutamate, norepinephrine, serotonin, and dopamine; and abnormalities in second messengers, protein
kinases, and apoptosis. Although each of these pathways offers potential therapeutic targets, pharmacologic manipulation of
the glutamatergic N-methyl-D-aspartate receptor pathway, alone or in combination with cholinergic therapies, is emerging as the next promising
strategy for the treatment of AD and vascular dementia. 相似文献
12.
Bi XH Lu CM Liu Q Zhang ZX Zhao HL Yu J Zhang JW 《Journal of neural transmission (Vienna, Austria : 1996)》2012,119(3):383-386
Calcium homeostasis is critical to amyloid beta precursor protein (APP) processing. Na+/Ca2+ exchanger (NCX) proteins play an important role in maintaining intracellular Na+ and Ca2+ homeostasis in the brain under physiological and pathological conditions. We sequenced a hyper-variable region in intron
2 of the Na+/Ca2+ exchanger 1 gene (NCX1), and investigated whether insertion/deletion variations in this region are associated with the occurrence for Alzheimer’s
disease (AD). Examining 413 AD patients and 361 healthy controls, we identified 3 insertion/deletion polymorphisms. No significant
differences of the allele and genotype frequencies were observed between the AD cases and the controls for any of the three
polymorphisms. However, among the AD patients whose age at onset (AAO) was 65 years or older (n = 299), carriers of a 14 bp insertion showed a lower average AAO (ins/ins and ins/del vs. del/del, 72.49 ± 5.17 vs. 74.28 ± 5.79,
p = 0.016). It suggested that this 14 bp insertion/deletion polymorphism might modulate AAO in late-onset AD patients. 相似文献
13.
Eugeniu Vieru Ayhan Köksal Belgin Mutluay Ayten Ceyhan Dirican Yavuz Altunkaynak Sevim Baybas 《Neurological sciences》2016,37(5):743-747
In this study, we aimed to investigate the association of the serum uric acid (UA) level with disease progression and l-Dopa treatment in PD (Parkinson’s disease) patients. Serum UA levels of 80 consecutive PD patients were measured and were matched according to age and sex with 80 healthy controls. The patients were divided into two subgroups according to the pharmaceutical treatment received. First group consisted of patients treated with l-Dopa and a dopamine agonist and the second group consisted of patients treated only with a dopamine agonist. The patients were divided into two other subgroups according to Hoehn and Yahr scale. First group consisted of patients at the first two stages and the second group included patients at the third and upper stages. PD patients were found to have significantly lower levels of serum UA than controls (p = 0.000). Serum UA levels were lower in the group under l-Dopa + dopamine agonist treatment and in patients at third and upper Hoehn and Yahr stages than the patients under only dopamine agonist treatment and in the patients at the first two stages (p = 0.000 and p = 0.000). Multivariate logistic regression showed that advanced stages (OR 0.65, CI 0.50–0.79, p = 0.000) and l-Dopa treatment (OR 1.08, CI 1.03–1.16, p = 0.001) were independently associated with low UA levels. Our study supports that there is an inverse relation between UA levels and l-Dopa treatment and PD stages, and high serum UA levels may decrease the oxidative stress taking part in the pathogenesis of PD. 相似文献
14.
Abramsson A Landgren S Zetterberg M Seibt Palmer M Minthon L Gustafson DR Skoog I Blennow K Zetterberg H 《Neuromolecular medicine》2011,13(2):160-166
Aggregation of amyloid-beta is one of the major characteristics in brains of patients with Alzheimer’s disease (AD). Although
several mechanisms behind the formation of such aggregates have been suggested the regulatory factors are still unknown. The
present study aimed at investigating the association of lysyl oxidase-like 1 (LOXL1) polymorphisms with AD diagnosis and cerebrospinal fluid biomarkers (CSF) for the disease. Proteins of the lysyl oxidase (LOX) family are involved in cross-linking extracellular matrix proteins to insoluble fibers and have been associated with neurodegenerative
diseases including AD. Genetic polymorphisms in LOXL1 (rs1048661, rs3825942, and rs2165241) have been linked to exfoliation syndrome and exfoliation glaucoma, conditions that
have shown association with AD. The polymorphisms were genotyped by Taqman allelic discrimination in a study sample including
AD patients (n = 318) and controls (n = 575). In a subgroup of the population, the polymorphisms were analyzed in relation to APOE ε4 genotype and to CSF (T-tau, P-tau, and Aβ1–42). No evidence for associations of these polymorphisms with risk for AD or any of the studied CSF biomarkers measured was
found. These results do not support LOXL1 as being a major risk gene for AD. 相似文献
15.
Anoushe Zhand Arezou Sayad Soudeh Ghafouri-Fard Shahram Arsang-Jang Mehrdokht Mazdeh Mohammad Taheri 《Neurological sciences》2018,39(11):1945-1953
Epilepsy is a brain disorder with a global prevalence of 1%. It has been attributed to genetics and environmental factors. Despite efforts to identify the molecular pathology of epilepsy, the underlying mechanism is not understood yet. This study was carried out to compare GRIN2B, BDNF, and IL-1β gene expressions in 50 patients suffering from generalized epilepsy with tonic-colonic seizures and 50 age- and sex-matched healthy subjects using TaqMan Real-time PCR. Our results demonstrated significant upregulation of these genes in people with epilepsy compared with healthy subjects. We also found a positive correlation between GRIN2B and BDNF expression (r2=0.4619, p?<?0.0001), BDNF and IL-1β expression (r2?=?0.515, p?<?0.0001), and GRIN2B and IL-1β gene expressions (r2?=?0.666, p?<?0.0001) which implies the possibility to estimate the expression level of these genes by assessment of expression of one of them. Considering the results of the previous animal studies which showed upregulation of these genes in brain tissues of epileptic animals, the expression levels of GRIN2B, BDNF, and IL-1β in blood samples might be related to their expression in brain samples. Future studies are needed to assess the role of these genes in the pathogenesis of epilepsy and evaluate whether altered expression of these genes along with imaging methods can facilitate subtyping the epilepsy. 相似文献
16.
Quadri M Cossu G Saddi V Simons EJ Murgia D Melis M Ticca A Oostra BA Bonifati V 《Neurogenetics》2011,12(3):203-209
Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD),
but they have not been found so far in patients with Parkinson’s disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate.
We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls.
One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated
PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group,
there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and
another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron
disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their
average onset age was 70.0 years (SD 9.4, range 51–79), which is later but not significantly different from that of the patients
who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be
directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD. 相似文献
17.
Phenotype analysis in patients with early onset Parkinson’s disease with and without <Emphasis Type="Italic">parkin</Emphasis> mutations 总被引:1,自引:0,他引:1
The data regarding whether parkin genotype attributes phenotypic variation are conflicting. Since the incidence of parkin mutations is very low in patients with an age at onset (AAO) of >40 years, previous studies have unfairly compared phenotypes
of two early onset Parkinson’s disease (EOPD) groups with different AAOs. Thus, we compared the clinical features between
patients with and without parkin mutations in EOPD with an AAO of ≤40 years. Of the 124 patients with EOPD with an AAO of ≤40 years who were recruited and
screened for parkin mutations, 84 completed assessments for comparison of the phenotype according to parkin genotype. Fourteen of the 84 subjects carried two parkin mutations; 6, a single mutation; and 64, no mutations. Patients with two mutations had significantly younger AAOs, longer
duration of PD, and more common family history than patients without parkin mutations. Otherwise, motor and nonmotor symptoms did not differ between them. Subgroup analysis of EOPD with an AAO of ≤35 years
revealed similar results. Phenotype of EOPD may depend on early AAOs rather than presence of parkin mutations. 相似文献
18.
Hoeppner J Wegrzyn M Thome J Bauer A Oltmann I Buchmann J Teipel S 《Journal of neural transmission (Vienna, Austria : 1996)》2012,119(5):605-612
Transcranial magnetic stimulation (TMS) provides evidence for facilitatory and inhibitory motor dysfunctions in Alzheimer's disease (AD). The corpus callosum (CC) is affected in AD already at early stages consistent with the hypothesis that AD patients exhibit alterations in transcallosally mediated motor inhibition (ipsilateral silent period, iSP). Therefore, here we aimed at investigating the integrity not only of intra-, but also of inter-hemispheric mechanisms of cortical motor excitability in AD. We determined the iSP, the resting motor threshold (RMT), and the amplitude of motor evoked potentials (MEP) in 19 AD patients and 19 healthy controls using single-pulse TMS. Furthermore, we used paired-pulse TMS to study the intra-cortical inhibition (ICI) and intra-cortical facilitation (ICF). All subjects underwent comprehensive neuropsychologic, clinical, and laboratory testing, and neuroimaging to exclude significant co-morbidity. In AD patients, the RMT was significantly reduced (Oneway-ANOVA). An analysis of covariance (ANCOVA) revealed a strong group specific interaction of the inhibitory interstimulus intervals (p = 0.005) with a reduced ICI in AD. Furthermore, we found a significantly prolonged iSP-latency (p = 0.003) in AD compared to controls, whereas the iSP-duration was not different. The iSP-latency correlated significantly with the ICI (ANCOVA) (p = 0.02). The ICF did not differ significantly between groups. Our data suggest comprehensive but still subclinical dysfunctions of motor cortical inhibition in mild to moderate clinical stages of AD with strong interactions of intra- and inter-hemispheric inhibitory phenomena. Future studies are needed to show the potential prognostic relevance of these findings for the further course of the disease. 相似文献
19.
Gerlach M Beck J Riederer P van den Buuse M 《Journal of neural transmission (Vienna, Austria : 1996)》2011,118(12):1727-1732
A central problem in the treatment of Parkinson’s disease (PD) is the development of motor disturbances like l-DOPA-induced dyskinesia (LID) after long-term treatment. Preclinical and clinical studies demonstrated that serotonin 5-HT1A receptor agonists attenuate this disabling motor side effect. The aim of this study was to investigate the ability of flibanserin
compared to buspirone to attenuate l-DOPA-sensitized contraversive circling in hemiparkinsonian rats, which is an animal model of LID. Both drugs have a preferential
affinity for the serotonin 5-HT1A receptors. Buspirone was in comparison because it was expected to have an effect in this model. Unilaterally 6-hydroxydopamine
lesioned rats were treated twice daily intraperitoneally (ip) with l-DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg) for 21 days (on days 1, 3, 5, 8, 11, 14, 17 and 21). On day 24,
l-DOPA-sensitized rats were treated ip 5 min prior to administration of l-DOPA methyl ester and benserazide with either saline (controls), 2.5, 5 and 10 mg/kg buspirone or flibanserin. Acute administration
of both flibanserin and buspirone, dose dependently, attenuated the increased contraversive circling. An almost complete inhibition
of the turning response was observed at 5 mg/kg buspirone and 10 mg/kg flibanserin. The current preclinical findings further
implicate the 5-HT1A receptor as a promising therapeutic target for the reduction of LID and predict a potential efficacy of flibanserin in the
treatment of LID in PD. 相似文献