Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the human embryo, from approximately 6 weeks gestational age (GA), dopaminergic (DA) neurons can be found in the ventral mesencephalon (VM). More specifically, the post-mitotic neurons are located in the ventral part of the tegmentum (VT), whereas no mature DA neurons are found in the neighboring dorsal part. We used Affymetrix HG-U133 GeneChip technology to compare genome-wide expression profiles of ventral and dorsal tegmentum from 8 weeks GA human embryos, in order to identify genes involved in specification, differentiation, and survival of mesencephalic DA (mDA) neurons. Known mDA marker genes including ALDH1A1, DAT1, VMAT2, TH, CALB1, NURR1, FOXA1, GIRK2, PITX3, RET, and DRD2 topped the list of 96 genes from HG-U133A with higher expression in VT, validating the experimental set-up. In addition, 28 probes from HG-U133B were identified whereof most are annotated to UniGene clusters with no gene associated or to genes of unknown function. Of these, the fifteen most regulated transcripts, representing changes down to 56% could be verified by quantitative real-time PCR (Q-PCR) on a developmental series of subdissected human embryonic and fetal brain material, resulting in not only a regional but also a temporal expression profile. This revealed a distinct DA-associated profile for in particular a putative transcription factor (FLJ45455) and the uncharacterized transmembrane proteins KIAA1145 and SLC10A4. The data presented here may help to device cell replacement and regenerative therapies for Parkinson's disease (PD).
 ...
PMID:Identification of novel genes regulated in the developing human ventral mesencephalon. 1647 50

Parkinson's disease (PD) is a progressive neurodegenerative disease with typical motor symptoms due to the preferential loss of midbrain dopaminergic (mDA) neurons in the Substantia nigra pars compacta. Several proteins of the homeodomain family are crucial for the development of mDA neurons. These proteins remain expressed into adulthood with largely unknown functions, but potentially influence mDA neuronal survival. To determine whether genetic variation in these genes plays a role in sporadic PD, we performed a genetic association study in a screening sample of 340 PD patients and 680 controls and a large replication sample of 669 PD patients and 669 controls using 54 single nucleotide polymorphisms in and around the Engrailed 1/2, PITX3, LMX1B and OTX2 genes. We provide evidence for a novel, strong and reproducible association of the PITX3 promoter SNP rs3758549: C>T (p=0.004) with PD. The C-allele appears to be a recessive risk allele with an estimated population frequency of 83%. An allele-dependent dysregulation of PITX3 expression might contribute to the susceptibility to PD.
 ...
PMID:The transcription factor PITX3 is associated with sporadic Parkinson's disease. 1790 80

PITX3 is a transcription factor of importance for the differentiation and survival of midbrain dopaminergic neurons, the gene of which is disrupted in a putative mouse model for Parkinson's disease (PD). The A-allele of a HapMap tagging SNP (rs4919621) that was genotyped in a population of 361 PD patients, 69 of which had early onset, and in 333 controls, was significantly more common in PD patients with an early age of onset when compared either to controls (p=0.002) or to PD patients with late onset (p=0.001). In contrast, a previous finding suggesting a SNP (rs3758549) in the putative promoter region of the PITX3 gene to be associated with PD could not be replicated.
 ...
PMID:PITX3 polymorphism is associated with early onset Parkinson's disease. 1842 Mar 8

Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson's disease. Several epigenetic and genetic strategies have been tested for long-term maintenance and expansion of these cells in vitro. Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon (hVM1) based on v-myc immortalization. The cells expressed neural stem cell and radial glia markers like nestin, vimentin and 3CB2 under proliferation conditions. After withdrawal of growth factors, proliferation and expression of v-myc were dramatically reduced and the cells differentiated into astrocytes, oligodendrocytes and neurons. hVM1 cells yield a large number of dopaminergic neurons (about 12% of total cells are TH+) after differentiation, which also produce dopamine. In addition to proneural genes (NGN2, MASH1), differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as: LMX1A, LMX1B, GIRK2, ADH2, NURR1, PITX3, VMAT2 and DAT, indicating that they retain their regional identity. Our data indicate that this cell line and its clonal derivatives may constitute good candidates for the study of development and physiology of human dopaminergic neurons in vitro, and to develop tools for Parkinson's disease cell replacement preclinical research and drug testing.
 ...
PMID:Generation and properties of a new human ventral mesencephalic neural stem cell line. 1932 51

Derivation of midbrain dopaminergic (DA) neurons from human embryonic stem (hES) cells has been of particular interest because of the clinical potential for DA neuron transplantation in patients with Parkinson's disease (PD). Several protocols for DA neuron differentiation from mouse embryonic stem cells and hES cells have been reported: however, protocols involving hES cells have yet to be improved. Here, we used a slightly modified stromal cell-derived inducing activity method, consisting four different culture stages, to show that KhES-1 cells differentiate into tyrosine hydroxylase (TH)-positive DA neurons. Quantitative real-time PCR analysis showed a marked induction of the DA neuron marker genes NURR1, paired-like homeodomain transcription factor 3 (PITX3), LIM homeobox transcription- factor 1, beta (LMX1B), engrailed-1 (EN1), dopamine transporter (DAT), and aromatic amino acid decarboxylase (AADC) during differentiation. Treatment with fibroblast growth factor (FGF)-20 and FGF-2 at the final differentiation stage induced the increase of DA neuron development-related transcription factors such as NURR1, PITX3, LMX1B, and EN1. FGF-20 and FGF-2 enhanced DA neuron differentiation from hES cell-derived neural progenitor cells directly without any soluble factors from PA6 cells. These results provide valuable information that will assist in efficient DA neuron differentiation from hES cells and for future transplant application.
 ...
PMID:Differentiation of dopaminergic neurons from human embryonic stem cells: modulation of differentiation by FGF-20. 1933 7

The transcription factors PITX3 and Engrailed 1 (EN1), among others, have been shown to play a crucial role in the maturation and survival of midbrain dopaminergic neurons. The degeneration of those neurons is the pathological hallmark in Parkinson's disease (PD). In a hypothesis-driven candidate gene approach, it has been recently shown that polymorphisms in the genes coding for PITX3 and EN1 are associated with sporadic PD. In a study on 365 patients with PD and 418 controls, we genotyped nine single nucleotide polymorphisms spanning the entire genomic region of PITX3 and EN1. Furthermore, we analyzed whether the genotype of these SNPs associate with the age of onset in PD. We found a strong association between the PITX3 promoter rs3758549 polymorphism and PD (p=0.0001), as well as an association between EN1 rs1438852 and PD (p=0.046). In particular, our highly significant findings regarding the association of rs3758549 reproduce the results of the initial report on transcription factor gene variants, providing further evidence for PITX3 and EN1 polymorphisms as potential genetic risk factors for sporadic PD.
 ...
PMID:Association of transcription factor polymorphisms PITX3 and EN1 with Parkinson's disease. 1934 44

PITX3 is a transcription factor important for the differentiation and survival of midbrain dopaminergic neurons during the development. Recent reports suggest that single nucleotide polymorphisms (SNP) in the gene may be associated with Parkinson's disease (PD). To verify their findings and to determine the nature of the association in a subset of our PD patients we have analyzed two PITX3 SNPs (rs2281983 and rs4919621) in 265 PD patients and compared them with 210 age-matched healthy controls. Our data show that the substitutions of C/T in SNP1 and A/T in SNP2 are significantly higher in PD, and this finding is even more robust in young onset and familial PD as compared with age-matched healthy controls. Our findings indicate that PITX3 may play a role in the pathogenesis of PD.
 ...
PMID:Transcription factor PITX3 gene in Parkinson's disease. 1939 14

Human neural stem cells derived from the ventral mesencephalon (VM) are powerful research tools and candidates for cell therapies in Parkinson disease. Previous studies with VM dopaminergic neuron (DAn) precursors indicated poor growth potential and unstable phenotypical properties. Using the model cell line hVM1 (human ventral mesencephalic neural stem cell line 1; a new human fetal VM stem cell line), we have found that Bcl-X(L) enhances the generation of DAn from VM human neural stem cells. Mechanistically, Bcl-X(L) not only exerts the expected antiapoptotic effect but also induces proneural (NGN2 and NEUROD1) and dopamine-related transcription factors, resulting in a high yield of DAn with the correct phenotype of substantia nigra pars compacta (SNpc). The expression of key genes directly involved in VM/SNpc dopaminergic patterning, differentiation, and maturation (EN1, LMX1B, PITX3, NURR1, VMAT2, GIRK2, and dopamine transporter) is thus enhanced by Bcl-X(L). These effects on neurogenesis occur in parallel to a decrease in glia generation. These in vitro Bcl-X(L) effects are paralleled in vivo, after transplantation in hemiparkinsonian rats, where hVM1-Bcl-X(L) cells survive, integrate, and differentiate into DAn, alleviating behavioral motor asymmetry. Bcl-X(L) then allows for human fetal VM stem cells to stably generate mature SNpc DAn both in vitro and in vivo and is thus proposed as a helpful factor for the development of cell therapies for neurodegenerative conditions, Parkinson disease in particular.
 ...
PMID:In vitro and in vivo enhanced generation of human A9 dopamine neurons from neural stem cells by Bcl-XL. 2010 70

MicroRNAs are small RNA sequences that negatively regulate gene expression by binding to the 3' untranslated regions of mRNAs. MiR-133b has been implicated in Parkinson's disease (PD) by a mechanism that involves the regulation of the transcription factor PITX3. The variation in these genes could contribute to the risk of developing PD. We searched for DNA variants in miR-133 and PITX3 genes in PD patients and healthy controls from Spain. We found common DNA variants in the three miR-133 genes. Genotyping of a first set of patients (n = 777) and controls (n = 650) showed a higher frequency of homozygous for a miR-133b variant (-90 del A) in PD-patients (6/575; 1%) than in healthy controls (0/650) (P = 0.03). However, this association was not confirmed in a second set of patients (1/250; 0.4%) and controls (2/210; 1%). No common PITX3 variants were associated with PD, although a rare missense change (G32S) was found in only one patient and none of the controls. In conclusion, we report the variation in genes of a pathway that has been involved in dopaminergic neuron differentiation and survival. Our work suggests that miR-133 and PITX3 gene variants did not contribute to the risk for PD.
 ...
PMID:Analysis of the Micro-RNA-133 and PITX3 genes in Parkinson's disease. 2046 68

The early development of dopaminergic pathways has been attributed importance for the aetiology of schizophrenia. Several transcription factors are involved in the survival and maturation of dopamine neurons, including LMX1A, LMX1B and PITX3. The possibility that polymorphisms in these genes may influence the development and/or the maintenance of dopaminergic neurons prompted us to investigate if five single nucleotide polymorphisms (SNPs) previously linked to Parkinson's disease are associated with this disorder. Preliminary evidence that genetic variation in LMX1A (rs6668493, rs4657411), LMX1B (rs10987386) and PITX3 (rs4919621) may increase the risk of developing schizophrenia is presented.
 ...
PMID:Preliminary evidence that polymorphisms in dopamine-related transcription factors LMX1A, LMX1B and PITX3 are associated with schizophrenia. 2057 Jun


1 2 3 4 Next >>