PRKN

Gene Summary

Gene:PRKN; parkin RBR E3 ubiquitin protein ligase
Aliases: PDJ, AR-JP, LPRS2, PARK2
Location:6q26
Summary:The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase parkin
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (36)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer Gene Expression Regulation
  • Chromosome Fragile Sites
  • Gene Expression Regulation
  • Brain Tumours
  • Neurons
  • Genetic Predisposition
  • Disease Models, Animal
  • Genetic Therapy
  • Oxidative Stress
  • Single Nucleotide Polymorphism
  • Western Blotting
  • DNA Sequence Analysis
  • DNA Primers
  • Apoptosis
  • Tumor Suppressor Gene
  • Protein-Serine-Threonine Kinases
  • Melanoma
  • Alzheimer Disease
  • Case-Control Studies
  • Statistics, Nonparametric
  • Mutation
  • Mitochondria
  • Neurodegenerative Diseases
  • Receptor, Melanocortin, Type 1
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Age of Onset
  • Spain
  • Lung Cancer
  • Gene Dosage
  • Genetic Variation
  • Missense Mutation
  • Gene Expression Profiling
  • Parkinson Disease
  • Oligonucleotide Array Sequence Analysis
  • Breast Cancer
  • Genotype
  • Brain Tumours
  • Base Sequence
  • Genome-Wide Association Study
  • Chromosome 6
  • Neuroblastoma
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PARK2 (cancer-related)

Sun L, Wu Q, Pei Y, et al.
Prenatal diagnosis and genetic discoveries of an intracranial mixed neuronal-glial tumor: A case report and literature review.
Medicine (Baltimore). 2016; 95(45):e5378 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Congenital intracranial tumors as a group are quite rare, representing only 0.5% to 1.5% of all pediatric brain neoplasms.
CASE REPORT: We reported a case of congenital mixed neuronal-glial tumor detected by ultrasound at 30 weeks of gestation. It showed that the tumor was 2.5 × 2.3 × 2.1 cm in size, located in the sellar region, regular shape, and slightly heterogeneous solid mass with a little cystic component. No color flow was present inside the tumor, but the peripheral encirclement by arterial circle of Willis. No other associated malformations were detected. Prenatal magnetic resonance imaging (MRI) which was taken subsequently confirmed the result of ultrasound and provided more detailed information such as fetal brain dysplasia.The fetal chromosomal karyotype analysis is normal. Single-nucleotide polymorphism (SNP)-based chromosomal microarray analysis (CMA) detected a 0.72-Mb duplication at 4q35.2 in fetus which was associated with epilepsy and cardiac anomalies. It also revealed a 0.13-Mb deletion at 6q26 located in PARK2 gene, and the mutation of the gene is known to be related to autosomal recessive juvenile Parkinson disease.The parents chose termination of pregnancy (TOP). The histological examination showed a mixed neuronal-glial tumor.
CONCLUSION: Prenatal detection of mixed neuronal-glial tumor is very rare. Ultrasound is of critical importance to detect the intracranial tumors, and MRI can give us some detailed information about the tumors. However, the precise histologic type was depended on the pathological examination. CMA should be necessary for the fetuses with congenital intracranial tumors, especially when the fetal chromosomal karyotype analysis is normal.

Al-Qahtani AA, Al-Anazi MR, Al-Zoghaibi FA, et al.
 PARK2 polymorphisms predict disease progression in patients infected with hepatitis C virus.
Ann Hepatol. 2016 Nov-Dec 2016; 15(6):824-833 [PubMed] Related Publications
 Background. The protein encoded by PARK2 gene is a component of the ubiquitin-proteasome system that mediates targeting of proteins for the degradation pathway. Genetic variations at PARK2 gene were linked to various diseases including leprosy, typhoid and cancer. The present study investigated the association of single nucleotide polymorphisms (SNPs) in the PARK2 gene with the development of hepatitis C virus (HCV) infection and its progression to severe liver diseases.
MATERIAL AND METHODS: A total of 800 subjects, including 400 normal healthy subjects and 400 HCV-infected patients, were analyzed in this study. The patients were classified as chronic HCV patients (group I), patients with cirrhosis (group II) and patients with hepatocellular carcinoma (HCC) in the context of cirrhosis (group III). DNA was extracted and was genotyped for the SNPs rs10945859, rs2803085, rs2276201 and rs1931223.
RESULTS: Among these SNPs, CT genotype of rs10945859 was found to have a significant association towards the clinical progression of chronic HCV infection to cirrhosis alone (OR = 1.850; 95% C. I. 1.115-3.069; p = 0.016) or cirrhosis and HCC (OR = 1.768; 95% C. I. 1.090-2.867; p value = 0.020).
CONCLUSION: SNP rs10945859 in the PARK2 gene could prove useful in predicting the clinical outcome in HCV-infected patients.

Haque M, Kendal JK, MacIsaac RM, Demetrick DJ
WSB1: from homeostasis to hypoxia.
J Biomed Sci. 2016; 23(1):61 [PubMed] Free Access to Full Article Related Publications
The wsb1 gene has been identified to be important in developmental biology and cancer. A complex transcriptional regulation of wsb1 yields at least three functional transcripts. The major expressed isoform, WSB1 protein, is a substrate recognition protein within an E3 ubiquitin ligase, with the capability to bind diverse targets and mediate ubiquitinylation and proteolytic degradation. Recent data suggests a new role for WSB1 as a component of a neuroprotective pathway which results in modification and aggregation of neurotoxic proteins such as LRRK2 in Parkinson's Disease, via an unusual mode of protein ubiquitinylation.WSB1 is also involved in thyroid hormone homeostasis, immune regulation and cellular metabolism, particularly glucose metabolism and hypoxia. In hypoxia, wsb1 is a HIF-1 target, and is a regulator of the degradation of diverse proteins associated with the cellular response to hypoxia, including HIPK2, RhoGDI2 and VHL. Major roles are to both protect HIF-1 function through degradation of VHL, and decrease apoptosis through degradation of HIPK2. These activities suggest a role for wsb1 in cancer cell proliferation and metastasis. As well, recent work has identified a role for WSB1 in glucose metabolism, and perhaps in mediating the Warburg effect in cancer cells by maintaining the function of HIF1. Furthermore, studies of cancer specimens have identified dysregulation of wsb1 associated with several types of cancer, suggesting a biologically relevant role in cancer development and/or progression.Recent development of an inducible expression system for wsb1 could aid in the further understanding of the varied functions of this protein in the cell, and roles as a potential oncogene and neuroprotective protein.

Klimczak PF, Ventury DH, Faucz FR, et al.
Association of a PARK2 Germline Variant and Epithelial Ovarian Cancer in a Southern Brazilian Population.
Oncology. 2016; 91(2):101-5 [PubMed] Article available free on PMC after 10/06/2017 Related Publications
Ovarian cancer (OC) is the eighth most common cancer among women in Brazil and seventh in the world population. OC has a high mortality rate and is difficult to diagnose. Currently, OC detection most often occurs at an advanced stage of the disease due to its silent progression, which contributes to the high mortality rate. Available genetic markers are not considered specifically enough for an initial and definite diagnosis. The association with new genes involved with OC can provide a better understanding of this pathology as well as contribute to the development of a marker scenario, providing an improvement in the treatment and survival of patients. The aim of this study was to examine the potential association between the PARK2 gene and epithelial ovarian cancer (EOC). Accordingly, we conducted a study for which 25 patients and 87 controls were recruited. Linkage disequilibrium analysis showed that the four studied tag SNPs (rs2803073, rs6930532, rs1040079, and rs2276201) were independent. Our results using the multivariate analysis between the additive and dominant model demonstrated that tag SNP rs2803073 of PARK2 is associated with susceptibility to EOC (p = 0.018, OR = 0.42). These findings suggest that hereditary variation in the PARK2 gene could influence EOC development mechanisms.

Sumi-Akamaru H, Beck G, Shinzawa K, et al.
High expression of α-synuclein in damaged mitochondria with PLA2G6 dysfunction.
Acta Neuropathol Commun. 2016; 4:27 [PubMed] Article available free on PMC after 10/06/2017 Related Publications
To clarify the role of α-synuclein (αSyn) in neuronal membrane remodeling, we analyzed the expression of αSyn in neurons with a dysfunction of PLA2G6, which is indispensable for membrane remodeling. αSyn/phosphorylated-αSyn (PαSyn) distribution and neurodegeneration were quantitatively estimated in PLA2G6-knockout (KO) mice, which demonstrate marked mitochondrial membrane degeneration. We also assessed the relationship between αSyn deposits and mitochondria in brain tissue from patients with PLA2G6-associated neurodegeneration (PLAN) and Parkinson's disease (PD), and quantitatively examined Lewy bodies (LBs) and neurons. The expression level of αSyn was elevated in PLA2G6-knockdown cells and KO mouse neurons. Strong PαSyn expression was observed in neuronal granules in KO mice before onset of motor symptoms. The granules were mitochondrial outer membrane protein (TOM20)-positive. Ultramicroscopy revealed that PαSyn-positive granules were localized to mitochondria with degenerated inner membranes. After symptom onset, TOM20-positive granules were frequently found in ubiquitinated spheroids, where PαSyn expression was low. Axons were atrophic, but the neuronal loss was not evident in KO mice. In PLAN neurons, small PαSyn-positive inclusions with a TOM20-positive edge were frequently observed and clustered into LBs. The surfaces of most LBs were TOM20-positive in PLAN and TOM20-negative in PD brains. The high proportion of LB-bearing neurons and the preserved neuronal number in PLAN suggested long-term survival of LB-bearing neurons. Elevated expression of αSyn/PαSyn in mitochondria appears to be the early response to PLA2G6-deficiency in neurons. The strong affinity of αSyn for damaged mitochondrial membranes may promote membrane stabilization of mitochondria and neuronal survival in neurons.

Liu S, Cui B, Dai ZX, et al.
Long Non-coding RNA HOTAIR Promotes Parkinson's Disease Induced by MPTP Through up-regulating the Expression of LRRK2.
Curr Neurovasc Res. 2016; 13(2):115-20 [PubMed] Related Publications
Homeobox (HOX) transcript antisense RNA (HOTAIR), as a long intergenic noncoding RNA (lincRNA), is known to be overexpressed in several cancers. However, the role of HOTAIR in Parkinson's disease (PD) remains unclear. A mouse model of PD was developed by intraperitoneal injection of MPTP (N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine). The expression of HOTAIR and LRRK2 (leucine-rich repeat kinase 2) were detected in the PD mice and in Human neuroblastoma cell lines SH-SY5Y pretreated with MPP+ (N-methyl-4-phenylpyridinium). The effect of HOTAIR on the expression of LRRK2 was examined in SH-SY5Y cells through overexpressing HOTAIR. A MTT (3- (4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay was performed to measure the cell viability of SH-SY5Y cells. si-HOTAIR (siRNA-HOTAIR) was utilized to investigate the effect of HOTAIR on the expression of LRRK2 in vivo. In this study, upregulation of HOTAIR and LRRK2 were found in the midbrain of PD mice induced by MPTP and in SH-SY5Y cells pretreated with MPP+. With the presence of HOTAIR overexpression in SH-SY5Y cells, the expression of LRRK2 was increased compared with that in the control. HOTAIR knockdown showed a protective effect on the cell viability of SH-SY5Y cells pretreated with MPP+, which was abrogated by overexpression of LRRK2. In mouse model of PD treated with si-HOTAIR, the expression of LRRK2 was decreased. In conclusion, high expression of HOTAIR promoted the onset of PD induced by MPTP. Moreover, the finding that HOTAIR promoted PD induced by MPTP through regulating LRRK2 expression could add our understanding of the molecular mechanisms in PD.

Siiskonen SJ, Zhang M, Li WQ, et al.
A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants.
Cancer Epidemiol Biomarkers Prev. 2016; 25(4):714-20 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: No GWAS on the risk of cutaneous squamous cell carcinoma (SCC) has been published. We conducted a multistage genome-wide association study (GWAS) to identify novel genetic loci for SCC.
METHODS: The study included 745 SCC cases and 12,805 controls of European descent in the discovery stage and 531 SCC cases and 551 controls of European ancestry in the replication stage. We selected 64 independent loci that showed the most significant associations with SCC in the discovery stage (linkage disequilibrium r(2) < 0.4) for replication.
RESULTS: Rs8063761 in the DEF8 gene on chromosome 16 showed the strongest association with SCC (P = 1.7 × 10(-9) in the combined set; P = 1.0 × 10(-6) in the discovery set and P = 4.1 × 10(-4) in the replication set). The variant allele of rs8063761 (T allele) was associated with a decreased expression of DEF8 (P = 1.2 × 10(-6)). Besides, we validated four other SNPs associated with SCC in the replication set, including rs9689649 in PARK2 gene (P = 2.7 × 10(-6) in combined set; P = 3.2 × 10(-5) in the discovery; and P = 0.02 in the replication), rs754626 in the SRC gene (P = 1.1 × 10(-6) in combined set; P = 1.4 × 10(-5) in the discovery and P = 0.02 in the replication), rs9643297 in ST3GAL1 gene (P = 8.2 × 10(-6) in combined set; P = 3.3 × 10(-5) in the discovery; and P = 0.04 in the replication), and rs17247181 in ERBB2IP gene (P = 4.2 × 10(-6) in combined set; P = 3.1 × 10(-5) in the discovery; and P = 0.048 in the replication).
CONCLUSION: Several genetic variants were associated with risk of SCC in a multistage GWAS of subjects of European ancestry.
IMPACT: Further studies are warranted to validate our finding and elucidate the genetic function of these variants. Cancer Epidemiol Biomarkers Prev; 25(4); 714-20. ©2016 AACR.

Rajagopalan S, Rane A, Chinta SJ, Andersen JK
Regulation of ATP13A2 via PHD2-HIF1α Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease.
J Neurosci. 2016; 36(4):1086-95 [PubMed] Related Publications
UNLABELLED: We previously reported that pharmacological inhibition of a class of enzymes known as prolyl hydroxylase domain proteins (PHDs) has neuroprotective effects in various in vitro and in vivo models of Parkinson's disease (PD). We hypothesized that this was due to inhibition of the PHD2 isoform, preventing it from hydroxylating the transcription factor hypoxia inducible factor 1 α (HIF1α), targeting it for eventual proteasomal degradation. HIF1α itself induces the transcription of various cellular stress genes, including several involved in iron metabolism. Although all three isoforms of PHD are expressed within vulnerable dopaminergic (DAergic) substantia nigra pars compacta neurons, only select downregulation of the PHD2 isoform was found to protect against in vivo neurodegenerative effects associated with the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These findings were corroborated in induced pluripotent stem cell-derived neurons, providing validation in a pertinent human cell model. PHD2 inhibition was found to result in increased expression of ATP13A2, mutation of which is responsible for a rare juvenile form of PD known as Kufor-Rakeb syndrome. Knockdown of ATP13A2 expression within human DAergic cells was found to abrogate restoration of cellular iron homeostasis and neuronal cell viability elicited by inhibition of PHD2 under conditions of mitochondrial stress, likely via effects on lysosomal iron storage. These data suggest that regulation of ATP13A2 by the PHD2-HIF1α signaling pathway affects cellular iron homeostasis and DAergic neuronal survival. This constitutes a heretofore unrecognized process associated with loss of ATP13A2 function that could have wide-ranging implications for it as a therapeutic target for PD and other related conditions.
SIGNIFICANCE STATEMENT: Reductions in PHD2 activity within dopaminergic neurons in vivo and in cultured human induced pluripotent stem cell-derived neurons protects against mitochondrial stress-induced neurotoxicity. Protective effects are dependent on downstream HIF-1α expression. Knockdown of ATP13A2, a gene linked to a rare juvenile form of Parkinson's disease and recently identified as a novel HIF1α target, was found to abrogate maintenance of cellular iron homeostasis and neuronal viability elicited by PHD2 inhibition in vivo and in cultured dopaminergic cells under conditions of mitochondrial stress. Mechanistically, this was due to ATP13A2's role in maintaining lysosomal iron stores. This constitutes a novel mechanism by which alterations in ATP13A2 activity may be driving PD-related neuropathology.

Disse M, Reich H, Lee PK, Schram SS
A Review of the Association Between Parkinson Disease and Malignant Melanoma.
Dermatol Surg. 2016; 42(2):141-6 [PubMed] Related Publications
BACKGROUND: An association between melanoma and Parkinson disease (PD) has been hinted at in the neurology and oncology literature since the 1970s after the initiation of levodopa (L-DOPA) therapy for PD. Given that L-DOPA is a substrate in melanin synthesis, there existed a concern that this therapy might cause melanoma.
OBJECTIVE: The objective was to research possible etiological links to explain the connection between PD and melanoma.
METHODS: A PubMed and Google Scholar literature search was performed using access provided by the University of Minnesota biomedical library.
RESULTS: Patients with PD have an overall decreased risk of cancer diagnoses. However, breast cancer and melanoma have an uncharacteristically high rate of co-occurrence with PD. Family history of melanoma and lighter hair and skin color confer a higher risk of developing PD, and having a first-degree relative with either disease conveys a significantly increased risk of developing the other. Other possible connections that have been explored include pigmentation genes in neural-derived cells, pesticides, MC1R polymorphisms, and abnormal cellular autophagy.
CONCLUSION: Although a link between PD and melanoma exists, the etiology of this link continues to be elusive. Both PD and melanoma are likely multifactorial diseases involving genetic and environmental risk factors.

Hu HH, Kannengiesser C, Lesage S, et al.
PARKIN Inactivation Links Parkinson's Disease to Melanoma.
J Natl Cancer Inst. 2016; 108(3) [PubMed] Related Publications
BACKGROUND: Melanoma incidence is higher in patients affected by Parkinson's disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression.
METHODS: An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fisher's exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided.
RESULTS: Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation.
CONCLUSION: Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases.

Sengupta D, Aich I, Bandyopadhyay S
Feature selection using feature dissimilarity measure and density-based clustering: application to biological data.
J Biosci. 2015; 40(4):721-30 [PubMed] Related Publications
Reduction of dimensionality has emerged as a routine process in modelling complex biological systems. A large number of feature selection techniques have been reported in the literature to improve model performance in terms of accuracy and speed. In the present article an unsupervised feature selection technique is proposed, using maximum information compression index as the dissimilarity measure and the well-known density-based cluster identification technique DBSCAN for identifying the largest natural group of dissimilar features. The algorithm is fast and less sensitive to the user-supplied parameters. Moreover, the method automatically determines the required number of features and identifies them. We used the proposed method for reducing dimensionality of a number of benchmark data sets of varying sizes. Its performance was also extensively compared with some other well-known feature selection methods.

Caputi FF, Carretta D, Lattanzio F, et al.
Proteasome subunit and opioid receptor gene expression down-regulation induced by paraquat and maneb in human neuroblastoma SH-SY5Y cells.
Environ Toxicol Pharmacol. 2015; 40(3):895-900 [PubMed] Related Publications
Paraquat (PQ) and maneb (MB) are able to induce neurotoxic effects by promoting α-synuclein (α-syn) aggregates and altering tyrosine hydroxylase (TH), thus increasing the risk of Parkinson's disease (PD). These pesticides promote neurotoxic effects also by affecting proteasome function that normally regulate protein turnover. We investigated the effects of the two pesticides exposure on multiple targets involved in PD, using SH-SY5Y cells. First, we evaluated TH and α-syn protein levels following PQ and MB cell exposure and a significant increase of these protein levels was observed. Subsequently, since a relationship between ubiquitin/proteasome and opioid receptors has been proposed, the effects of pesticides on their gene expression have been investigated. A decrease of β1 and Rpt3 proteasome subunit mRNA levels, together with the μ and δ opioid receptor down-regulation, was detected. The reported alterations, here simultaneously observed, help to clarify the involvement of multiple biological markers implicated in PD, often separately evaluated.

Lee J, Ham S, Lee MH, et al.
Dysregulation of Parkin-mediated mitophagy in thyroid Hürthle cell tumors.
Carcinogenesis. 2015; 36(11):1407-18 [PubMed] Related Publications
Abnormal accumulation of defective mitochondria is the hallmark of oncocytes, which are frequently observed in thyroid Hürthle cell lesions. Autophagy is an essential cellular catabolic mechanism for the degradation of dysfunctional organelles and has been implicated in several human diseases. It is yet unknown how autophagic turnover of defective mitochondria in Hürthle cell tumors is regulated. We characterized the expression patterns of molecular markers including Beclin1, LC3, PINK1 and Parkin, which are required for autophagy or mitophagy, in human oncocytic lesions of the thyroid. To undertake mechanistic studies, we investigated autophagy and mitophagy using XTC.UC1 cells, the only in vitro model of Hürthle cell tumors. Beclin1 and LC3 were highly expressed in oncocytes of Hürthle cell tumors. XTC.UC1 showed autophagic responses to starvation and rapamycin treatment, whereas they displayed ineffective activation of mitophagy, which is triggered by the coordinated action of PINK1 and Parkin in response to CCCP. This resulted in a decreased turnover of abnormal mitochondria. The mechanisms underlying defective mitophagy and mitochondrial turnover were investigated by genetic analysis of the PARK2 gene in XTC.UC1 and Hürthle cell tumor tissues. XTC.UC1 and several tumors harbored the V380L mutation, resulting in dysfunctional autoubiquitination and decreased E3 ligase activity. Consistently, oncocytes in Hürthle cell tumors displayed comparable expression of PINK1 but decreased Parkin expression in comparison to normal thyrocytes. The introduction of wild-type Parkin sensitized XTC.UC1 to death induced by CCCP. This study provides a possible etiological basis for oncocytic formation in heterogeneous Hürthle cell tumors through insufficient mitophagy leading to ineffective turnover of aberrant mitochondria caused by dysfunctional Parkin-mediated pathways of mitochondria quality control.

Wang ZH, Zhang JL, Duan YL, et al.
MicroRNA-214 participates in the neuroprotective effect of Resveratrol via inhibiting α-synuclein expression in MPTP-induced Parkinson's disease mouse.
Biomed Pharmacother. 2015; 74:252-6 [PubMed] Related Publications
BACKGROUNDS AND AIMS: MicroRNAs (miRNAs) have been reported to be involved in degenerative disorders including Parkinson's disease (PD). α-synuclein expression is strong associated with the pathogenesis of PD. In the present study, we investigated whether the regulation of α-synuclein expression by miR-214 is the potential mechanism underlying the neuroprotective effect of Resveratrol.
METHODS: The PD mouse model was established with the injection of MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and the human neuroblastoma cell line, SH-SY5Y, was administrated with MPP+.
RESULTS: The midbrain of PD mice and MPP+ treated SH-SY5Y cells had the lower expression levels of miR-214 and higher mRNA and protein expression of α-synuclein, which were reversed by Resveratrol administration. MiR-214 mimic down-regulated expression of α-synuclein and its 3'-UTR activity, while the levels were up-regulated by miR-214 inhibitor. In addition, the cell viability, elevated by Resveratrol, was also decreased by miR-214 inhibitor or overexpressed α-synuclein. In vivo, miR-214 inhibitor down-regulated TH+ cells of ipsilateral and up-regulated α-synuclein expression compared with the group treated with Resveratrol.
CONCLUSION: The loss of miR-214 in PD resulted in the increase of α-synuclein expression, which was the potential mechanism underlying the neuroprotective effects of Resveratrol.

Barrett MT, Anderson KS, Lenkiewicz E, et al.
Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer.
Oncotarget. 2015; 6(28):26483-93 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio ≥ 1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis.

Liu QX, Zheng H, Deng XF, et al.
Status of the Parkinson's disease gene family expression in non-small-cell lung cancer.
World J Surg Oncol. 2015; 13:238 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The purpose of this study is to detect the Parkinson's disease gene family mRNA relative expression in the non-small-cell lung cancer (NSCLC) tumor tissue and analyze the association between tumor characteristics and the Parkinson's disease gene family.
METHODS: Tumor tissue and tumor-adjacent tissue of 114 NSCLC patients were collected and SYBR quantitative analysis was used to detect the relative expression level of nine Parkinson's disease gene mRNAs. Then, paired sample test, two-sided Student's t-test, or two-sided Wilcoxon rank sum test was performed to analyze the mRNA relative expression level of nine Parkinson's disease gene mRNAs in different gender, tumor histology, and tumor stage.
RESULTS: Overexpression in the tumors was detected in 46/114 (40.35%) PARK1/4, 74/114 (64.91%) PARK2, 104/114 (91.23%) PARK5, 95/114 (83.33%) PARK6, 80/114 (70.18%) PARK7, 55/114 (48.25%) PARK8, 100/114 (87.72%) PARK9, 55/114 (48.25%) PARK15, and 99/114 (86.84%) glucocerebrosidase (GBA). Five genes PARK5 (91.23%), PARK6 (83.33%), PARK7 (70.18%), PARK9 (87.72%), and GBA (86.84%) were supposed to be overexpressed in the lung tumor tissues compared with tumor-adjacent tissues. There was no significant difference in PARK1/4, PARK2, PARK5, PARK9, and GBA mRNA expression by different tumor stage, whereas, PARK6, PARK7, PARK8, and PARK15 mRNA expression were found to have significant difference in the comparison of different tumor stages. The expression of PARK6 (P=0.01, P=0.03) and PARK15 (P<0.001, P<0.001) were significantly higher in stages I and II when compared with stage III, respectively. NSCLC patients in stage I showed the higher expression PARK7 compared to the patients in stage II (P=0.003).
CONCLUSIONS: The high expression of PARK6, PARK7, and PARK15 might lead to the occurrence of a primary NSCLC tumor, and the tumor with a decreasing expression of these three genes tends to be stages II and III. The results of our study indicate that the Parkinson's disease gene family may be a potential marker for the prediction of NSCLC.

Cai Y, An SS, Kim S
Mutations in presenilin 2 and its implications in Alzheimer's disease and other dementia-associated disorders.
Clin Interv Aging. 2015; 10:1163-72 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Alzheimer's disease (AD) is the most common form of dementia. Mutations in the genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a systematic review of studies describing the mutations identified in PSEN2. Most PSEN2 mutations were detected in European and in African populations. Only two were found in Korean populations. Interestingly, PSEN2 mutations appeared not only in AD patients but also in patients with other disorders, including frontotemporal dementia, dementia with Lewy bodies, breast cancer, dilated cardiomyopathy, and Parkinson's disease with dementia. Here, we have summarized the PSEN2 mutations and the potential implications of these mutations in dementia-associated disorders.

Moussa CE
Parkin Is Dispensable for Mitochondrial Function, but Its Ubiquitin Ligase Activity Is Critical for Macroautophagy and Neurotransmitters: Therapeutic Potential beyond Parkinson's Disease.
Neurodegener Dis. 2015; 15(5):259-70 [PubMed] Related Publications
Parkin biology has emerged as an exciting area of pharmaceutical development for several human diseases, including cancer and neurodegeneration. Parkin's role is multifaceted in human health and disease and its function affecting major cellular quality control mechanisms, including the ubiquitin-proteasome and autophagy-lysosome systems, is critical in the maintenance of cellular homeostasis. Loss of Parkin function due to aging, protein instability and gene mutations is manifest in a number of human diseases, contributing to the validation of this protein as a therapeutic target. Parkin activation to mobilize cellular quality control mechanisms and counteract dyshomeostasis is a highly desirable area for therapeutic development. The elucidation of Parkin's crystal structure and better understanding of possible posttranslational modifications (i.e. phosphorylation, ubiquitination, etc.) that regulate Parkin's enzymatic activity suggest that this protein is a therapeutic drug target in many human diseases. Here we review Parkin's role in health and disease and discuss the effects of self-ubiquitination and deubiquitination on Parkin activity. This review provides further evidence showing the longitudinal effects of Parkin deletion on mitochondrial function, oxidative stress and neurotransmitter balance in vivo using high-frequency (1)H/(13)C NMR spectroscopy.

Cox TM, Rosenbloom BE, Barker RA
Gaucher disease and comorbidities: B-cell malignancy and parkinsonism.
Am J Hematol. 2015; 90 Suppl 1:S25-8 [PubMed] Related Publications
Data emerging from the International Collaborative Gaucher Group (ICGG) Gaucher Registry together with other contemporary clinical surveys have revealed a close association between Gaucher disease and non-Hodgkin's B-cell lymphoma and myeloma and Gaucher disease and Parkinson's disease. Several possible explanations for increased B-cell proliferation and neoplasia in Gaucher disease have been proposed, including the possible influence of sphingosine (derived from the extra lysosomal metabolism of glucosylceramide), gene modifiers, splenectomy and immune system deregulation induced by cytokines, chemokines, and hydrolases released from Gaucher cells. Parkinson's disease is frequently seen in the otherwise-healthy relatives of Gaucher disease patients leading to the finding that GBA mutations represent a genetic risk factor for Parkinson's disease. The mechanism of the association between GBA mutations and Parkinson's disease has yet to be elucidated but the pathogenesis appears distinct from that of Gaucher disease. Several pathogenic pathways have been proposed including lysosomal and/or mitochondrial dysfunction. The effect of Gaucher disease specific therapies on the incidence of cancer or Parkinson's disease are not clear and will likely be evaluated in future ICGG Gaucher Registry studies.

Ariga H
Common mechanisms of onset of cancer and neurodegenerative diseases.
Biol Pharm Bull. 2015; 38(6):795-808 [PubMed] Related Publications
Onset of cancer and neurodegenerative disease occurs by abnormal cell growth and neuronal cell death, respectively, and the number of patients with both diseases has been increasing in parallel with an increase in mean lifetime, especially in developed countries. Although both diseases are sporadic, about 10% of the diseases are genetically inherited, and analyses of such familial forms of gene products have contributed to an understanding of the molecular mechanisms underlying the onset and pathogenesis of these diseases. I have been working on c-myc, a protooncogene, for a long time and identified various c-Myc-binding proteins that play roles in c-Myc-derived tumorigenesis. Among these proteins, some proteins have been found to be also responsible for the onset of neurodegenerative diseases, including Parkinson's disease, retinitis pigmentosa and cerebellar atrophy. In this review, I summarize our findings indicating the common mechanisms of onset between cancer and neurodegenerative diseases, with a focus on genes such as DJ-1 and Myc-Modulator 1 (MM-1) and signaling pathways that contribute to the onset and pathogenesis of cancer and neurodegenerative diseases.

Lin DC, Xu L, Chen Y, et al.
Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma.
Cancer Res. 2015; 75(9):1815-27 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PARK2 (PARKIN) is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of Parkinsonism and human malignancies, and its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, whereas depletion of PARK2 promoted cell proliferation. PARK2 attenuated both Wnt- and EGF-stimulated pathways through downregulating the intracellular level of β-catenin and EGFR. Notably, PARK2 physically interacted with both β-catenin and EGFR. We further found that PARK2 promoted the ubiquitination of these two proteins in an E3 ligase activity-dependent manner. Finally, inspired by these newly identified tumor-suppressive functions of PARK2, we tested and proved that combination of small-molecule inhibitors targeting both Wnt-β-catenin and EGFR-AKT pathways synergistically impaired glioma cell viability. Together, our findings uncover novel cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma.

Naushad SM, Vijayalakshmi SV, Rupasree Y, et al.
Multifactor dimensionality reduction analysis to elucidate the cross-talk between one-carbon and xenobiotic metabolic pathways in multi-disease models.
Mol Biol Rep. 2015; 42(7):1211-24 [PubMed] Related Publications
Putatively functional polymorphisms of one-carbon and xenobiotic metabolic pathways influence susceptibility for wide spectrum of diseases. The current study was aimed to explore gene-gene interactions among these two metabolic pathways in four diseases i.e. breast cancer, systemic lupus erythematosus (SLE), coronary artery disease (CAD) and Parkinson's disease (PD). Multifactor dimensionality reduction analysis was carried out on four case-control datasets. Cross-talk was observed between one-carbon and xenobiotic pathways in breast cancer (RFC 80 G>A, COMT H108L and TYMS 5'-UTR 28 bp tandem repeat) and SLE (CYP1A1 m1, MTRR 66 A>G and GSTT1). Gene-gene interactions within one-carbon metabolic pathway were observed in CAD (GCPII 1561 C>T, SHMT 1420 C>T and MTHFR 677 C>T) and PD (cSHMT 1420 C>T, MTRR 66 A>G and RFC1 80 G>A). These interaction models showed good predictability of risk for PD (The area under the receiver operating characteristic curve (C) = 0.83) and SLE (C = 0.73); and moderate predictability of risk for breast cancer (C = 0.64) and CAD (C = 0.63). Cross-talk between one-carbon and xenobiotic pathways was observed in diseases with female preponderance. Gene-gene interactions within one-carbon metabolic pathway were observed in diseases with male preponderance.

Xiong D, Wang Y, Kupert E, et al.
A recurrent mutation in PARK2 is associated with familial lung cancer.
Am J Hum Genet. 2015; 96(2):301-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PARK2, a gene associated with Parkinson disease, is a tumor suppressor in human malignancies. Here, we show that c.823C>T (p.Arg275Trp), a germline mutation in PARK2, is present in a family with eight cases of lung cancer. The resulting amino acid change, p.Arg275Trp, is located in the highly conserved RING finger 1 domain of PARK2, which encodes an E3 ubiquitin ligase. Upon further analysis, the c.823C>T mutation was detected in three additional families affected by lung cancer. The effect size for PARK2 c.823C>T (odds ratio = 5.24) in white individuals was larger than those reported for variants from lung cancer genome-wide association studies. These data implicate this PARK2 germline mutation as a genetic susceptibility factor for lung cancer. Our results provide a rationale for further investigations of this specific mutation and gene for evaluation of the possibility of developing targeted therapies against lung cancer in individuals with PARK2 variants by compensating for the loss-of-function effect caused by the associated variation.

Tell-Marti G, Puig-Butille JA, Potrony M, et al.
The MC1R melanoma risk variant p.R160W is associated with Parkinson disease.
Ann Neurol. 2015; 77(5):889-94 [PubMed] Related Publications
Epidemiological studies have reported the co-occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender- and age-adjusted p = 0.009, Bonferroni-corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population.

Gao G, Smith DI
WWOX, large common fragile site genes, and cancer.
Exp Biol Med (Maywood). 2015; 240(3):285-95 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
WWOX is a gene that spans an extremely large chromosomal region. It is derived from within chromosomal band 16q23.2 which is a region with frequent deletions and other alterations in a variety of different cancers. This chromosomal band also contains the FRA16D common fragile site (CFS). CFSs are chromosomal regions found in all individuals which are highly unstable. WWOX has also been demonstrated to function as a tumor suppressor that is involved in the development of many cancers. Two other highly unstable CFSs, FRA3B (3p14.2) and FRA6E (6q26), also span extremely large genes, FHIT and PARK2, respectively, and these two genes are also found to be important tumor suppressors. There are a number of interesting similarities between these three large CFS genes. In spite of the fact that they are derived from some of the most unstable chromosomal regions in the genome, they are found to be highly evolutionarily conserved and the chromosomal region spanning the mouse homologs of both WWOX and FHIT are also CFSs in mice. Many of the other CFSs also span extremely large genes and many of these are very attractive tumor suppressor candidates. WWOX is therefore a member of a very interesting family of very large CFS genes.

Di Sante G, Pestell TG, Casimiro MC, et al.
Loss of Sirt1 promotes prostatic intraepithelial neoplasia, reduces mitophagy, and delays PARK2 translocation to mitochondria.
Am J Pathol. 2015; 185(1):266-79 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Prostatic intraepithelial neoplasia is a precursor to prostate cancer. Herein, deletion of the NAD(+)-dependent histone deacetylase Sirt1 induced histological features of prostatic intraepithelial neoplasia at 7 months of age; these features were associated with increased cell proliferation and enhanced mitophagy. In human prostate cancer, lower Sirt1 expression in the luminal epithelium was associated with poor prognosis. Genetic deletion of Sirt1 increased mitochondrial superoxide dismutase 2 (Sod2) acetylation of lysine residue 68, thereby enhancing reactive oxygen species (ROS) production and reducing SOD2 activity. The PARK2 gene, which has several features of a tumor suppressor, encodes an E3 ubiquitin ligase that participates in removal of damaged mitochondria via mitophagy. Increased ROS in Sirt1(-/-) cells enhanced the recruitment of Park2 to the mitochondria, inducing mitophagy. Sirt1 restoration inhibited PARK2 translocation and ROS production requiring the Sirt1 catalytic domain. Thus, the NAD(+)-dependent inhibition of SOD2 activity and ROS by SIRT1 provides a gatekeeper function to reduce PARK2-mediated mitophagy and aberrant cell survival.

Krishna A, Biryukov M, Trefois C, et al.
Systems genomics evaluation of the SH-SY5Y neuroblastoma cell line as a model for Parkinson's disease.
BMC Genomics. 2014; 15:1154 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The human neuroblastoma cell line, SH-SY5Y, is a commonly used cell line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this cell line is often used as a cellular model for Parkinson's disease, the relevance of this cellular model in the context of Parkinson's disease (PD) and other neurodegenerative diseases has not yet been systematically evaluated.
RESULTS: We have used a systems genomics approach to characterize the SH-SY5Y cell line using whole-genome sequencing to determine the genetic content of the cell line and used transcriptomics and proteomics data to determine molecular correlations. Further, we integrated genomic variants using a network analysis approach to evaluate the suitability of the SH-SY5Y cell line for perturbation experiments in the context of neurodegenerative diseases, including PD.
CONCLUSIONS: The systems genomics approach showed consistency across different biological levels (DNA, RNA and protein concentrations). Most of the genes belonging to the major Parkinson's disease pathways and modules were intact in the SH-SY5Y genome. Specifically, each analysed gene related to PD has at least one intact copy in SH-SY5Y. The disease-specific network analysis approach ranked the genetic integrity of SH-SY5Y as higher for PD than for Alzheimer's disease but lower than for Huntington's disease and Amyotrophic Lateral Sclerosis for loss of function perturbation experiments.

Miners JS, Renfrew R, Swirski M, Love S
Accumulation of α-synuclein in dementia with Lewy bodies is associated with decline in the α-synuclein-degrading enzymes kallikrein-6 and calpain-1.
Acta Neuropathol Commun. 2014; 2:164 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Kallikrein-6 and calpain-1 are amongst a small group of proteases that degrade α-synuclein. We have explored the possibility that reduction in the level or activity of these enzymes contributes to the accumulation of α-synuclein in Lewy body diseases. We measured calpain-1 activity by fluorogenic activity assay, kallikrein-6 level by sandwich ELISA, and levels of α-synuclein and α-synuclein phosphorylated at serine 129 (α-synuclein-P129), in post-mortem brain tissue in pure dementia with Lewy bodies (DLB, n=12), Alzheimer's disease (AD, n=20) and age-matched controls (n=19). Calpain-1 activity was significantly reduced in DLB within the cingulate and parahippocampal cortex, regions with highest α-synuclein and α-synuclein-P129 load, and correlated inversely with the levels of α-synuclein and α-synuclein-P129. Calpain-1 was unaltered in the thalamus and frontal cortex, regions with less α-synuclein pathology. Kallikrein-6 level was reduced in the cingulate cortex in the DLB cohort, and correlated inversely with α-synuclein and α-synuclein-P129. Kallikrein-6 was also reduced in DLB in the thalamus but not in relation to α-synuclein or α-synuclein-P129 load and was unaltered in the frontal and parahippocampal cortex. In SH-SY5Y cells overexpressing wild-type α-synuclein there was partial co-localisation of kallikrein-6 and calpain-1 with α-synuclein, and siRNA-mediated knock-down of kallikrein-6 and calpain-1 increased the amount of α-synuclein in cell lysates. Our results indicate that reductions in kallikrein-6 and calpain-1 may contribute to the accumulation of α-synuclein in DLB.

Eschbach J, von Einem B, Müller K, et al.
Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization.
Ann Neurol. 2015; 77(1):15-32 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
OBJECTIVE: Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson disease (PD), with accumulating evidence that prefibrillar oligomers and protofibrils are the pathogenic species in PD and related synucleinopathies. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a key regulator of mitochondrial biogenesis and cellular energy metabolism, has recently been associated with the pathophysiology of PD. Despite extensive effort on studying the function of PGC-1α in mitochondria, no studies have addressed whether PGC-1α directly influences oligomerization of α-syn or whether α-syn oligomers impact PGC-1α expression.
MATERIALS AND METHODS: We tested whether pharmacological or genetic activation of PGC-1α or PGC-11α knockdown could modulate the oligomerization of α-syn in vitro by using an α-syn -fragment complementation assay.
RESULTS: In this study, we found that both PGC-1α reference gene (RG-PGC-1α) and the central nervous system (CNS)-specific PGC-1α (CNS-PGC-1α) are downregulated in human PD brain, in A30P α-syn transgenic animals, and in a cell culture model for α-syn oligomerization. Importantly, downregulation of both RG-PGC-1α and CNS-PGC-1α in cell culture or neurons from RG-PGC-1α-deficient mice leads to a strong induction of α-syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG-PGC-1α reduced α-syn oligomerization and rescued α-syn-mediated toxicity.
INTERPRETATION: Based on our results, we propose that PGC-1α downregulation and α-syn oligomerization form a vicious circle, thereby influencing and/or potentiating each other. Our data indicate that restoration of PGC-1α is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies.

Karim S, Mirza Z, Kamal MA, et al.
Gene expression analysis approach to establish possible links between Parkinson's disease, cancer and cardiovascular diseases.
CNS Neurol Disord Drug Targets. 2014; 13(8):1334-45 [PubMed] Related Publications
Non-communicable chronic diseases have been apparently established as threat to human health, and are currently the world's main killer. Cardiovascular diseases (CVD), cancer, diabetes and neurodegenerative diseases are collectively amounting to more than 60% of non-communicable disease burden across world. Tremendous advancements in healthcare enabled us to fight several health problems primarily infectious diseases. However, this increased longevity where in many cases an individual suffers from several such chronic diseases simultaneously, making treatment complex. Finding whether diseases can coexist in an individual by chance or there exists a possible association between them is vital. Our goal is to establish possible existing link among CVD, cancer and Parkinson's disease (PD) for better understanding of the associated molecular network. In this study, we integrated multiple dataset retrieved from the National Centre for Biotechnology Information's Gene Expression Omnibus database, and took a systems-biology approach to compare and distinguish the molecular network associated with PD, cancer and CVD. We identified 230, 308 and 1619 differentially expressed genes for CVD, cancer and PD dataset respectively using cut off p value<0.5 and fold change>2. We integrated these data with known pathways using Ingenuity Pathway Analysis tool and found following common pathways associated with all three diseases to be most affected; epithelial adherens junction signaling, remodelling of epithelial adherens junctions, role of BRCA1 in DNA damage response, sphingomyelin metabolism, 3- phosphoinositide biosynthesis, acute myeloid leukemia signaling, type I diabetes mellitus signaling, agrin interactions at neuromuscular junction, role of IL-17A in arthritis, and antigen presentation pathways. In conclusion, CVD, cancer and PD appear tightly associated at molecular level.

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