Parkinson's Disease Samples Research Articles

Elevated Plasma microRNA-105-5p Level in Patients With Idiopathic Parkinson's Disease: A Potential Disease Biomarker.

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which still lacks a biomarker to aid in diagnosis and to differentiate diagnosis at the early stage of the disease. microRNAs (miRNAs) are small and evolutionary conserved non-coding RNAs that are involved in post-transcriptional gene regulation. Several miRNAs have been proposed as potential biomarkers in several diseases. In the present study, we screened miRNAs using a network vulnerability analysis, to evaluate their potential as PD biomarkers. We first extracted miRNAs that were differentially expressed between PD and healthy controls (HC) samples. Then we constructed the PD-specific miRNA-mRNA network and screened miRNA biomarkers using a new bioinformatics model. With this model, we identified miR-105-5p as a putative biomarker for PD. Moreover, we measured miR-105-5p levels in the plasma of patients with idiopathic PD (IPD) (n = 319), neurological disease controls (NDC, n = 305) and HC (n = 273) using reverse transcription real-time quantitative PCR (RT-qPCR). Our data clearly demonstrated that the plasma miR-105-5p level in IPD patients was significantly higher than those of HC (251%, p < 0.001) and NDC (347%, p < 0.001). There was no significant difference in miR-105-5p expression between IPD patients with or without anti-PD medications. Interestingly, we found that the plasma miR-105-5p expression level may be able to differentiate IPD from parkinsonian syndrome, essential tremor and other neurodegenerative diseases. We believe that a change in the plasma miR-105-5p level is a potential biomarker for IPD.

Factor Structure of the Ways of Coping Questionnaire in Parkinson's Disease.

The Ways of Coping Questionnaire (WCQ) is used extensively in health research, but the measurement properties and suitability of the WCQ for people with Parkinson's disease (PD) have not been psychometrically assessed. If the WCQ does not align with its original 8-factor structure in a PD population, the use of the WCQ subscales may not be appropriate. The present study used confirmatory factor analysis (CFA), exploratory factor analysis (EFA), and multiple-group EFA to determine the ideal factor structure of the WCQ in a PD sample. The original 8 factors of the WCQ were not reproduced. EFA revealed a 6-factor structure, including Distancing, Faith, Avoidance, Seeking Social Support, Planful Problem Solving, and Confrontive coping. As motor symptom severity may impact coping, the stability of the 6-factor structure was examined across motor symptom severity (mild and moderate), remaining consistent. Higher levels of overall motor severity were associated with increased use of faith and avoidance style coping. These findings suggest that the 6-factor structure of the WCQ may be more appropriate for assessing coping styles in PD.

State anxiety predicts cognitive performance in patients with Parkinson's disease.

Anxiety is common in Parkinson's disease (PD) and frequently a comorbidity that appears alongside nonmotor symptoms such as cognitive deficits; however, the relationship between anxiety and cognition in PD remains poorly understood. The aim of this study was to investigate the relationship between anxiety and specific cognitive domains (e.g., attention/working memory, executive functions, memory, language, and visuospatial function). A total of 48 individuals with PD and 18 healthy controls were assessed using the State Trait Anxiety Inventory along with a comprehensive neuropsychological battery. Hierarchical multiple regression analysis was used to examine whether trait and/or state anxiety predicted deficits in overall cognitive function (Montreal Cognitive Assessment) and/or specific individual cognitive domains in the PD and healthy control samples while controlling for covariates such as age, depression (Geriatric Depression Scale), and Unified Parkinson's disease Rating Scale motor-subsection-III (PD only). Results showed that state anxiety in PD significantly predicted performance across an array of cognitive domains, such as attention/working memory, executive functioning, memory, and language, whereas trait anxiety was a predictor only for executive functioning. In contrast, there was no significant relationship between state anxiety and visuospatial ability Conclusions: Overall, these findings highlight that performance in particular cognitive domains are associated with anxiety in PD. Thus, it may be critically important to consider and quantify the contribution of anxiety to cognitive performance when diagnosing and treating dementia and/or mild cognitive impairments in PD. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Pooled-DNA target sequencing of Parkinson genes reveals novel phenotypic associations in Spanish population.

Eighteen loci and several susceptibility genes have been related to Parkinson's disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p<0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31.82%). Seven novel variants were identified. Interestingly, most variants were found in PARK2 and PINK1 genes, whereas SNCA and DJ-1 variants were rare. Validated variants were also genotyped in Spanish healthy controls (n= 597). Carriers of heterozygous PARK2 variants presented earlier disease onset and showed dementia more frequently. PD subjects carrying 2 variants at different genes (1.42%) had an earlier age of onset and a predominantly akinetic-rigid PD phenotype (55.6%, p < 0.05), suggesting that the accumulation of genetic risk variants could modify PD phenotype.

Critical Roles of Glutaredoxin in Brain Cells-Implications for Parkinson's Disease.

Glutaredoxin (Grx)1, an evolutionarily conserved and ubiquitous enzyme, regulates redox signal transduction and protein redox homeostasis by catalyzing reversible S-glutathionylation. Grx1 plays different roles in different cell types. In Parkinson's disease (PD), Grx1 regulates apoptosis signaling in dopaminergic neurons, so that loss of Grx1 leads to increased cell death; in microglial cells, Grx1 regulates proinflammatory signaling, so that upregulation of Grx1 promotes cytokine production. Here we examine the regulatory roles of Grx1 in PD with a view toward therapeutic innovation. Recent Advances: In postmortem midbrain PD samples, Grx1 was decreased relative to controls, specifically within dopaminergic neurons. In Caenorhabditis elegans models of PD, loss of the Grx1 homologue led to exacerbation of the neurodegenerative phenotype. This effect was partially relieved by overexpression of neuroprotective DJ-1, consistent with regulation of DJ-1 content by Grx1. Increased GLRX copy number in PD patients was associated with earlier PD onset; and Grx1 levels correlated with levels of proinflammatory tumor necrosis factor-α in mouse and human brain samples. In vitro studies showed Grx1 to be upregulated on proinflammatory activation of microglia. Direct overexpression of Grx1 increased microglial activation; silencing Grx1 diminished activation. Grx1 upregulation in microglia corresponded to increased neuronal cell death in coculture. Overall, these studies identify competing roles of Grx1 in PD etiology. The dilemma regarding Grx1 as a PD therapeutic target is whether to stimulate its upregulation for neuroprotection or inhibit its proinflammatory activity. Further investigation is needed to understand the preponderant role of Grx1 regarding dopaminergic neuronal survival.

Identification of crucial genes associated with Parkinson's disease using microarray data

The present study aimed to examine potential crucial genes associated with Parkinson's disease (PD) in addition to the interactions and regulators of these genes. The chip data (GSE7621) were obtained from the Gene Expression Omnibus and standardized using the robust multi‑array average in the Affy package of R software. The differentially expressed genes (DEGs) were then screened using the Samr package with a false discovery rate (FDR) <0.05 and |log2 fold change (FC)|>1. Crucial PD‑associated genes were predicted using the Genetic Association Database in the Database for Annotation, Visualization and Integrated Discovery and sequence alignment. Furthermore, transcription factors (TFs) of the crucial PD‑associated genes were predicted, and protein‑protein interactions (PPIs) between the crucial PD‑associated genes were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins. Additionally, another dataset of PD was used to validate the expression of crucial PD‑associated genes. A total of 670 DEGs (398 upregulated and 272 downregulated genes) were identified in the PD samples. Of these, 10 DEGs enriched in pathways associated with the nervous system were predicted to be crucial in PD, including C‑X‑C chemokine receptor type 4 (CXCR4), deleted in colorectal cancer (DCC) and NCL adaptor protein 2 (NCK2). All 10 genes were associated with neuron development and differentiation. They were simultaneously modulated by multiple TFs, including GATA, E2F and E4 promoter‑binding protein 4. The PPI networks showed that DCC and CXCR4 were hub proteins. The DCC‑netrin 1‑roundabout guidance receptor 2‑slit guidance ligand 1 interaction pathway, and several genes, including TOX high mobility group box family member 4, kinase insert domain receptor and zymogen granule protein 16B, which interacted with CXCR4, were novel findings. Additionally, CXCR4 and NCK2 were upregulated in another dataset (GSE8397) of PD. These genes, interactions of proteins and TFs may be important in the progression of PD.

Cutaneous Alpha-Synuclein From Paraffin Embedded Autopsy Specimens in Parkinson's Disease.

Parkinson disease (PD) is neurodegenerative disorder characterized by tremor, rigidity and bradykinesia and pathologically by the deposition of alpha-synuclein within different tissues. We, and others, have reported the detection of cutaneous alpha-synuclein in individuals with PD. The goal of the present study was to detect alpha-synuclein deposition by immunohistochemical staining of skin samples in pathologically confirmed cases of PD. Post-mortem skin biopsy samples from 11 individuals with PD, and 5 non-synucleinopathy control subjects were paraffin embedded and stained for total alpha-synuclein and protein gene product 9.5. Alpha-synuclein deposition was greater in both scalp and abdominal skin biopsy PD samples compared to control samples in pilomotor nerves (P < 0.05), sudomotor nerves (P < 0.05) and vasomotor nerves (P < 0.05). Deposition of alpha-synuclein in scalp and abdominal tissue did not correlate with age, duration of PD, or severity of PD. There is greater deposition of alpha-synuclein within pilomotor, sudomotor and vasomotor nerve fibers of paraffin embedded samples from autopsy confirmed cases of PD compared to control samples. However, assessment of alpha-synuclein deposition in post-mortem paraffin embedded tissue has many limitations and the utility of this technique in clinical and research studies is uncertain.

Identification of key genes and pathways in Parkinson's disease through integrated analysis.

Parkinson's disease (PD) is a progressive, degenerative neurological disease, typically characterized by tremors and muscle rigidity. The present study aimed to identify differentially expressed genes (DEGs) between patients with PD and healthy patients, and clarify their association with additional biological processes that may regulate factors that lead to PD. An integrated analysis of publicly available Gene Expression Omnibus datasets of PD was performed. DEGs were identified between PD and normal blood samples. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses, as well as protein-protein interaction (PPI) networks were used to predict the functions of identified DEGs. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to validate the predicted expression levels of identified DEGs in whole blood samples obtained from patients with PD and normal healthy controls. A total of 292DEGs were identified between the PD and normal blood samples. Of these, 156 genes were significantly upregulated and 136 genes were significantly downregulated in PD samples following integrated analysis of four PD expression datasets. The 10 most upregulated and downregulated genes were used to construct a PPI network, where ubiquitin C-terminal hydrolase L1 (UCHL1), 3-phosphoinositide dependent protein kinase 1 (PDPK1) and protein kinase cAMP-activated catalytic subunit β (PRKACB) demonstrated the highest connectivity in the network. DEGs were significantly enriched in amoebiasis, vascular smooth muscle contraction, and the Wnt and calcium signaling pathways. The expression levels of significant DEGs, UCHL1, PDPK1 and PRKACB were validated using RT-qPCR analysis. The findings revealed that UCHL1 and PDPK1 were upregulated and PRKACB was downregulated in patients with PD when compared with normal healthy controls. In conclusion, the results indicate that the significant DEGs, including UCHL1, PDPK1 and PRKACB may be associated with the development of PD. In addition, these factors may be involved in various signaling pathways, including amoebiasis, vascular smooth muscle contraction and the Wnt and calcium signaling pathways.

Mitochondrial respiratory chain disorganization in Parkinson's disease-relevant PINK1 and DJ1 mutants

Brain mitochondrial complex I (CI) damage is associated with the loss of the dopaminergic neurons of the Substantia Nigra in Parkinson's Disease (PD) patients. However, whether CI inhibition is associated with any alteration of the mitochondrial respiratory chain (MRC) organization in PD patients is unknown. To address this issue, here we analyzed the MRC by blue native gel electrophoresis (BNGE) followed by western blotting, in mitochondria purified from fibroblasts of patients harboring PD-relevant Pink1 mutations. We found a decrease in free CI, and in free versus supercomplexes (SCs)-assembled CI in PD; however, free complex III (CIII) was only modestly affected, whereas its free versus SCs-assembled forms decreased. Interestingly, complex IV (CIV) was considerably lost in the PD samples. These results were largely confirmed in mitochondria isolated from cultured neurons from Pink1-/- mice, and in cultured neurons and forebrain samples from the PD-related Dj1-/- mice. Thus, besides CI damage, the MRC undergoes a profound structural remodeling in PD likely responsible for the energetic inefficiency and mitochondrial reactive oxygen species (mROS) over-production observed in this disease.

Systematic analysis of microarray datasets to identify Parkinson's disease‑associated pathways and genes.

In order to investigate commonly disturbed genes and pathways in various brain regions of patients with Parkinson's disease (PD), microarray datasets from previous studies were collected and systematically analyzed. Different normalization methods were applied to microarray datasets from different platforms. A strategy combining gene co-expression networks and clinical information was adopted, using weighted gene co-expression network analysis (WGCNA) to screen for commonly disturbed genes in different brain regions of patients with PD. Functional enrichment analysis of commonly disturbed genes was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Co-pathway relationships were identified with Pearson's correlation coefficient tests and a hypergeometric distribution-based test. Common genes in pathway pairs were selected out and regarded as risk genes. A total of 17 microarray datasets from 7 platforms were retained for further analysis. Five gene coexpression modules were identified, containing 9,745, 736, 233, 101 and 93 genes, respectively. One module was significantly correlated with PD samples and thus the 736 genes it contained were considered to be candidate PD-associated genes. Functional enrichment analysis demonstrated that these genes were implicated in oxidative phosphorylation and PD. A total of 44 pathway pairs and 52 risk genes were revealed, and a risk gene pathway relationship network was constructed. Eight modules were identified and were revealed to be associated with PD, cancers and metabolism. A number of disturbed pathways and risk genes were unveiled in PD, and these findings may help advance understanding of PD pathogenesis.

Factors associated with life satisfaction in Parkinson's disease

To identify factors associated with life satisfaction (LS) in people with Parkinson's disease (PD), including a specific focus on those with late-stage PD. The study included 251 persons with PD (median age 70years; PD duration 8years). Analyses involved the total sample and a subsample with late-stage PD, that is Hoehn and Yahr stages IV and V (n=62). LS was assessed with item 1 of the Life Satisfaction Questionnaire (LiSat-11). Simple logistic regression analyses were performed for both the total sample and for the subsample with late-stage PD. For the total sample, a multivariable logistic regression analysis was also performed. In the total sample, 12 of the 20 independent variables were significantly associated with LS: need of help with ADL; walking difficulties; number of non-motor symptoms (NMS); fatigue; depressive symptoms; general self-efficacy; motor symptoms; pain; PD severity; freezing episodes; gender (woman); and fluctuations. When controlling for age and gender in the multivariable logistic regression model, depressive symptoms were negatively associated with high LS and general self-efficacy was positively associated with high LS. In late-stage PD, simple logistic regression analyses (controlling for age and gender) identified the following factors as associated with LS: number of NMS, general self-efficacy, walking difficulties and fatigue. This study provides new knowledge on factors associated with LS in a PD sample, including those with late-stage PD. As the ultimate goal for PD care should be improvement in LS, the results have direct clinical implication.

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson's disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects. To explore this possibility, we used dual-tracer positron emission tomography to quantify regional cerebral blood flow and metabolic activity in 28 PD subjects (14 LID, 14 non-LID), scanned before and during intravenous levodopa infusion. Levodopa-mediated dissociation was most prominent in the posterior putamen (P < 0.0001) and greater in LID than in non-LID and test-retest subjects. Strikingly, LID subjects also showed increased sensorimotor cortex (SMC) activity in the baseline, unmedicated state. Imaging data from an independent PD sample (106 subjects) linked these differences to loss of mesocortical dopamine terminals in advanced patients. In aggregate, the data suggest that LID results from an overactive vasomotor response to levodopa in the putamen on a background of disease-related increases in SMC activity. LID may thus be amenable to treatment that modulates the function of these 2 regions.

Clinically relevant cut-off values for the Parkinson's Disease Sleep Scale-2 (PDSS-2): a validation study

BackgroundSleep disturbances are a major problem encountered by neurologists attending Parkinson's disease (PD) patients. The Parkinson's Disease Sleep Scale-2 (PDSS-2) assesses a wide spectrum of disease-specific sleep problems and is easy to administer as a patient self-rating scale. The validation study showed that the scale is reliable, valid, and precise. Until now, however, only one Japanese study has assessed cut-off scores to define poor sleepers. ObjectivesIn this context we aimed to determine the PDSS-2 cut-off values that define a sleep disturbance severe enough to require referral of the patient to a sleep center or the need for specific treatment. MethodsInpatients with idiopathic PD consecutively admitted to our hospital were enrolled. Patients completed the PDSS-2. The attending physician, who was blinded to the PDSS-2 results, but familiar with the patients' history and current disease status, completed a questionnaire consisting of two general questions on the presence of PD-specific and non-PD related sleep problems. Statistical analysis was performed to determine cut-off values for the PDSS-2 and correlation with the physician's evaluation of sleep disturbance severity. A natural cohort of non-PD patients with sleep disorders represented the control group. ResultsThe sample consisted of 52 (56%) men and 41 (44%) women with an average age of 69.22 ± 8.74 years. PDSS-2 showed a sensitivity of 77.6% and a specificity of 74.3% in relation to physician's evaluation of PD-specific sleep problems. According to the physician's evaluation, PD-specific sleep disturbances occurred in 62% of the patients. 83% of patients with PDSS-2 scores ≥18 had clinically relevant sleep disturbances compared to only 33% of PD patients with scores <18. The severity of PD-specific sleep problems was well correlated with the PDSS-2 total score (r = 0.49). ConclusionsTo our knowledge, this is the first study to define PDSS-2 cut-off values for the severity of sleep disturbances in a European PD sample. Our study shows that scores ≥18 define clinically relevant PD-specific sleep disturbances.

Electrophysiological assessment of nociception in patients with Parkinson's disease: A multi-methods approach

ObjectiveNociceptive abnormalities indicating increased pain sensitivity have been reported in patients with Parkinson's disease (PD). The disturbances are mostly responsive to dopaminergic (DA) treatment; yet, there are conflicting results. The objective of the present study was to investigate pain processing and nociception in PD patients in a more comprehensive manner than previous studies. For this purpose, a multi-methods approach was used in order to monitor different levels of the central nervous system (spinal, subcortical-vegetative, cortical). MethodsThe heat-pain threshold, contact-heat evoked brain potentials (CHEPs) and sympathetic skin responses (SSR), nociceptive flexion responses (NFR) and subjective pain ratings were measured in 23 idiopathic PD patients both in the Off-phase (without DA medication) and On-phase (after DA medication intake) as well as in 23 healthy controls. ResultsCompared to controls, PD patients showed decreased heat-pain thresholds only in the Off and tentatively increased NFR amplitudes in both phases. We found no between-group differences for the CHEPs, the NFR threshold/latency or the pain ratings. Yet, SSR amplitudes/frequencies were decreased and latencies were increased in PD patients in both phases. Correlations between CHEPs amplitudes and pain ratings were found only in controls. DiscussionIncreased pain sensitivity (heat-pain threshold) in the Off which normalizes in the On argues for DA induced dysfunctions of the nigrostriatal pain loops with the basal ganglia as main circuit in our PD sample. Dysfunctions of the subcortical-vegetative parameters despite of inconspicuous cortical nociception suggest disturbances of the central or peripheral innervation of sympathetic branches with coincidently intact ascending pathways in the PD group.

Genetic Mutation Analysis of Parkinson's Disease Patients Using Multigene Next-Generation Sequencing Panels.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting millions of people. Genome-wide association studies (GWAS) have found>25 genetic risk factors and at least 15 loci directly associated with PD. Recent advances in new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent platform, make multigene sequencing cheaper, faster, and more reliable. Our objective was to test the power of this next-generation sequencing technology to analyze large samples by screening the majority of the most relevant PD-related genes known for single and compound mutations. To archive a rapid, robust, and cost-effective genetic analysis of a PD cohort, we designed a multiplex, polymerase chain reaction (PCR)-based primer panel to amplify and sequence coding exons of 15 PD-associated genes (SNCA, LRRK2, PARK2, PINK1, PARK7, GIGYF2, ATP13A2, UCHL1, PLA2G6, FBXO7, EIF4G1, VPS35, ACMSD, APOE, and GBA). We conducted parallel sequencing using the Ion Torrent Personal Genome Machine(®) system to detect mutations in 92 blood DNA samples from PD patients. After bioinformatics analysis and filtering, 95.13% coverage of the targeted region was obtained at>40-fold mean coverage. The results revealed 44 previously documented variants in these 15 genes, with five revealed as pathogenic. We also discovered six novel variants, five of which had an in silico prediction of being pathogenic. Benchtop next-generation sequencing is a powerful method for genetic screening for PD. Our results indicated that it yielded a high frequency of discovery (66%; n=92) of variants in carriers from an enriched Spanish PD sample.

Molecular Mechanism of Regulation of MTA1 Expression by Granulocyte Colony-stimulating Factor

Parkinson disease (PD) is a neurodegenerative disorder with loss of dopaminergic neurons of the brain, which results in insufficient synthesis and action of dopamine. Metastasis-associated protein 1 (MTA1) is an upstream modulator of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and hence MTA1 plays a significant role in PD pathogenesis. To impart functional and clinical significance to MTA1, we analyzed MTA1 and TH levels in the substantia nigra region of a large cohort of human brain tissue samples by Western blotting, quantitative PCR, and immunohistochemistry. Our results showed that MTA1 and TH levels were significantly down-regulated in PD samples as compared with normal brain tissue. Correspondingly, immunohistochemistry analysis for MTA1 in substantia nigra sections revealed that 74.1% of the samples had a staining intensity of <6 in the PD samples as compared with controls, 25.9%, with an odds ratio of 8.54. Because of the clinical importance of MTA1 established in PD, we looked at agents to modulate MTA1 expression in neuronal cells, and granulocyte colony-stimulating factor (G-CSF) was chosen, due to its clinically proven neurogenic effects. Treatment of the human neuronal cell line KELLY and acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model with G-CSF showed significant induction of MTA1 and TH with rescue of phenotype in the mouse model. Interestingly, the observed induction of TH was compromised on silencing of MTA1. The underlying molecular mechanism of MTA1 induction by G-CSF was proved to be through induction of c-Fos and its recruitment to the MTA1 promoter.

Kognitives Training bei Parkinson-Patienten – eine neue Therapieoption?

Cognitive impairment is a frequent and clinically relevant symptom in patients with Parkinson's disease (PD). Given that pharmacological therapy options are limited, non-pharmacological interventions for the prevention and treatment of cognitive impairment in PD patients are attracting increasing interest. This review summarizes the current state of research regarding cognition-based interventions in PD patients. Eleven randomized controlled studies (RCT) were found in a systematic literature search, all of which used cognitive training (CT). These studies and a recently published meta-analysis demonstrate that especially executive and memory functions can be enhanced by CT in PD patients. Future studies examining CT or cognitive stimulation should include large PD samples with well-defined cognitive inclusion criteria so that clear therapy recommendations can be defined for PD patients without cognitive dysfunctions, those with mild cognitive impairment, and those with dementia.

Investigation of Long Non-coding RNA Expression Profiles in the Substantia Nigra of Parkinson's Disease.

Genetics is considered as an important risk factor in the pathological changes of Parkinson's disease (PD). Substantia nigra (SN) is thought to be the most vulnerable area in this process. In recent decades, however, few related long non-coding RNAs (lncRNAs) in the SN of PD patients had been identified and the functions of those lncRNAs had been studied even less. In this study, we sought to investigate the lncRNA expression profiles and their potential functions in the SN of PD patients. We screened lncRNA expression profiles in the SN of PD patients using the lncRNA mining approach from the ArrayExpress database, which included GSE20295. The samples were from 11 of PD and 14 of normal tissue samples. We identified 87 lncRNAs that were altered significantly in the SN during the occurrence of PD. Among these lncRNAs, lncRNA AL049437 and lncRNA AK021630 varied most dramatically. AL049437 was up-regulated in the PD samples, while AK021630 was down-regulated. Based on the results, we focused on the potential roles of the two lncRNAs in the pathogenesis of PD by the knockdown of the expression of AL049437 or AK021630 in human neuroblastoma SH-SY5Y cell line. Results indicated that the reduction in AL049437 level increased cell viability, mitochondrial transmembrane potential (Δψm), mitochondrial mass, and tyrosine hydroxylase (TyrH) secretion. By contrast, the knockdown of AK021630 resulted in the opposite effect. Based on these results, we speculated that lncRNA AL049437 likely contributed to the risk of PD, while lncRNA AK021630 likely inhibited the occurrence of PD.

Monte Carlo cross-validation analysis screens pathway cross-talk associated with Parkinson's disease.

We purposed to identify underlying functional pathway cross-talk in Parkinson's disease (PD) through Monte Carlo cross-validation analysis. Microarray data set of E-GEOD-6613 was downloaded from ArrayExpress database. First, the identification of differentially expressed genes (DEGs) was implemented, following by extracting the potential disrupted pathway enriched by DEGs. In addition, a discriminating score (DS) was computed based on the distribution of gene expression levels by quantifying their pathway cross-talk for each pair of pathways. Furthermore, random forest (RF) classification model was utilized to identify the top ten paired pathways with high AUC between PD and healthy control samples using the tenfold cross-validation method. Finally, Monte Carlo cross-validation was repeated 50 times to explore the best pairs of pathways. After quantile normalization, a total of 9331 genes with higher than 0.25-fold quantile average across all samples were obtained. Totally, 42 DEGs and 19 differential pathways enriched from DEGs were identified. We then ranked each pathway according to their AUC values, the pair of pathways, phosphatidylcholine biosynthesis I, and PPAR signaling obtained the best AUC value of 0.942. Moreover, the paired pathways of mTOR signaling and CD28 signaling in T helper cells had higher AUC value of 0.837 in five bootstraps. Two paired pathways, including phosphatidylcholine biosynthesis I and PPAR signaling, as well as mTOR signaling and CD28 signaling in T helper cells were able to accurately classify PD and healthy control samples. Significantly, these paired pathways might be underlying biomarkers for early diagnosis and therapy of PD.

Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.

BackgroundMost sequencing studies in Parkinson’s disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815).ResultsDisease-causing variants in the SNCA,LRRK2 and PARK2 genes were found in 2 % of PD patients. The LRRK2, p.G2019S mutation was found in 0.6 % of sporadic PD and 4.8 % of familial PD cases. Gene-based analysis suggests that additional variants in the LRRK2 gene also contribute to PD risk. The SNCA duplication was found in 0.8 % of familial PD patients. Novel variants were found in 0.8 % of PD cases and 0.6 % of controls. Heterozygous Gaucher disease-causing mutations in the GBA gene were found in 7.1 % of PD patients. Here, we established that the GBA variant (p.T408M) is associated with PD risk and age at onset. Additionally, gene-based and single-variant analyses demostrated that GBA gene variants (p.L483P, p.R83C, p.N409S, p.H294Q and p.E365K) increase PD risk.ConclusionsOur data suggest that the impact of additional untested coding variants in the GBA and LRRK2 genes is higher than previously estimated. Our data also provide compelling evidence of the existence of additional untested variants in the primary Mendelian and PD GWAS genes that contribute to the genetic etiology of sporadic PD.