Trophoblast glycoprotein is a new candidate gene for Parkinson's disease.
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ABSTRACT:
SUBMITTER: Park S
PROVIDER: S-EPMC8651753 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Backgroundtrophoblast glycoprotein (Tpbg), a 72-kDa transmembrane glycoprotein, is known to regulate the phenotypes of epithelial cells by modifying actin organization and cell motility. Recently, a microarray study showed that Tpbg is upregulated in Thy1 glomerulonephritis (Thy1 GN). We hypothesized that Tpbg regulates cytoskeletal rearrangement and modulates phenotypic alteration in podocytes under pathological conditions.Methodswe examined Tpbg expression in Thy1 GN and Tpbg function in mouse podocytes.Resultswe demonstrated that Tpbg is upregulated in the injured podocytes of Thy1 GN. In vitro, immunofluorescence studies revealed that Tpbg colocalized with the focal adhesion protein, vinculin, in parallel with stress fiber formation. This colocalization was observed even when actin filaments were depolymerized with cytochalasin D. Tpbg localization at focal adhesions was induced by dominant-active RhoA and suppressed by the ROCK1 inhibitor Y-26732. In addition, transforming growth factor-β increased Tpbg expression at focal adhesions concurrently with rearrangement of stress fibers. Stress fiber formation was suppressed in differentiated podocytes transfected with full-length Tpbg. Furthermore, knockdown of Tpbg using small interfering RNA decreased podocyte motility.Conclusionour findings suggest a novel role of Tpbg in the phenotypic alteration of injured podocytes, and we accordingly propose a new mechanism of glomerular injury in glomerulonephritis.
| S-EPMC2992649 | biostudies-literature
Project description:Combining large-scale gene expression approaches and bioinformatics may provide insights into the molecular variability of biological processes underlying neurodegeneration. To identify novel candidate genes and mechanisms, we conducted a multiregional gene expression analysis in postmortem brain. Gene arrays were performed utilizing Affymetrix HG U133 Plus 2.0 gene chips. Brain specimens from 21 different brain regions were taken from Parkinson's disease (PD) (n = 22) and normal aged (n = 23) brain donors. The rationale for conducting a multiregional survey of gene expression changes was based on the assumption that if a gene is changed in more than one brain region, it may be a higher probability candidate gene compared to genes that are changed in a single region. Although no gene was significantly changed in all of the 21 brain regions surveyed, we identified 11 candidate genes whose pattern of expression was regulated in at least 18 out of 21 regions. The expression of a gene encoding the mitochondria ribosomal protein S6 (MRPS6) had the highest combined mean fold change and topped the list of regulated genes. The analysis revealed other genes related to apoptosis, cell signaling, and cell cycle that may be of importance to disease pathophysiology. High throughput gene expression is an emerging technology for molecular target discovery in neurological and psychiatric disorders. The top gene reported here is the nuclear encoded MRPS6, a building block of the human mitoribosome of the oxidative phosphorylation system (OXPHOS). Impairments in mitochondrial OXPHOS have been linked to the pathogenesis of PD.
| S-EPMC6032441 | biostudies-literature
Project description:BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder. The pathological hallmark of the disease is degeneration of midbrain dopaminergic neurons. Genetic association studies have linked 13 human chromosomal loci to Parkinson's disease. Identification of gene(s), as part of the etiology of Parkinson's disease, within the large number of genes residing in these loci can be achieved through several approaches, including screening methods, and considering appropriate criteria. Since several of the identified Parkinson's disease genes are expressed in substantia nigra pars compact of the midbrain, expression within the neurons of this area could be a suitable criterion to limit the number of candidates and identify PD genes. METHODS: In this work we have used the combination of findings from six rodent transcriptome analysis studies on the gene expression profile of midbrain dopaminergic neurons and the PARK loci in OMIM (Online Mendelian Inheritance in Man) database, to identify new candidate genes for Parkinson's disease. RESULTS: Merging the two datasets, we identified 20 genes within PARK loci, 7 of which are located in an orphan Parkinson's disease locus and one, which had been identified as a disease gene. In addition to identifying a set of candidates for further genetic association studies, these results show that the criteria of expression in midbrain dopaminergic neurons may be used to narrow down the number of genes in PARK loci for such studies.
| S-EPMC2929225 | biostudies-literature
Project description:Parkinson's disease is now the most rapidly growing neurodegenerative disease worldwide. It is therefore critical to identify which factors, and to what extent, contribute to the multifactorial etiology of Parkinson's disease. Here, we address two interesting elements from the perspective of genetics, namely (a) the estimated age of several genetic risk factors related to Parkinson's disease; and (b) the relative contribution of genetics to the etiology of Parkinson's disease, as derived from twin studies. Based on these two perspectives, we argue that most genetic risk factors are by themselves insufficient to explain the majority of Parkinson's disease, and that environmental factors are required for these genetic factors to become pathophysiologically relevant.
| S-EPMC10741370 | biostudies-literature
Project description:Genetic variation modulating risk of sporadic Parkinson’s disease (PD) has been primarily explored through genome wide association studies (GWAS). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal timepoints. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a novel postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including known PD genes and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1 null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research.
2018-01-31 | GSE108020 | GEO
Project description:BackgroundParkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Most cases are sporadic, however familial cases do exist. We examined 12 families with familial Parkinson's disease ascertained at the Movement Disorder clinic at the Oregon Health Sciences University for genetic linkage to a number of candidate loci. These loci have been implicated in familial Parkinson's disease or in syndromes with a clinical presentation that overlaps with parkinsonism, as well as potentially in the pathogenesis of the disease.MethodsThe examined loci were PARK3, Parkin, DRD (dopa-responsive dystonia), FET1 (familial essential tremor), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), Ret, DAT1 (the dopamine transporter), Nurr1 and Synphilin-1. Linkage to the alpha-synuclein gene and the Frontotemporal dementia with parkinsonism locus on chromosome 17 had previously been excluded in the families included in this study. Using Fastlink, Genehunter and Simwalk both parametric and model-free non-parametric linkage analyses were performed.ResultsIn the multipoint parametric linkage analysis lod scores were below -2 for all loci except FET1 and Synphilin-1 under an autosomal dominant model with incomplete penetrance. Using non-parametric linkage analysis there was no evidence for linkage, although linkage could not be excluded. A few families showed positive parametric and non-parametric lod scores indicating possible genetic heterogeneity between families, although these scores did not reach any degree of statistical significance.ConclusionsWe conclude that in these families there was no evidence for linkage to any of the loci tested, although we were unable to exclude linkage with both parametric and non-parametric methods.
| S-EPMC184377 | biostudies-literature
Project description:The expression of 5T4/trophoblast glycoprotein was evaluated in several histological subtypes of soft tissue sarcoma (STS) to determine whether the prevalence and level of expression of this membrane-associated glycoprotein is sufficient for use in targeted therapies. Tumor tissue microarrays containing cores from different histological subtypes of STS were stained using a standardized immunohistochemical staining method to detect 5T4; the level of staining was assessed using a semi-quantitative scoring method. No 5T4 staining was seen in the angiosarcomas and liposarcomas investigated in this study. 5T4 staining in the other STS subtypes was seen in more than 50% of cases, warranting further investigation into whether this antigen could evoke an anti-tumor immune response or can be used as target for the delivery of more potent toxins through antibody drug conjugates.
| S-EPMC8508483 | biostudies-literature
Project description:We recently identified the leucine-rich repeat (LRR) adhesion protein, trophoblast glycoprotein (TPBG), as a novel PKCα-dependent phosphoprotein in retinal rod bipolar cells (RBCs). Since TPBG has not been thoroughly examined in the retina, this study characterizes the localization and expression patterns of TPBG in the developing and adult mouse retina using two antibodies, one against the N-terminal LRR domain and the other against the C-terminal PDZ-interacting motif. Both antibodies labeled RBC dendrites in the outer plexiform layer and axon terminals in the IPL, as well as a putative amacrine cell with their cell bodies in the inner nuclear layer (INL) and a dense layer in the middle of the inner plexiform layer (IPL). In live transfected HEK293 cells, TPBG was localized to the plasma membrane with the N-terminal LRR domain facing the extracellular space. TPBG immunofluorescence in RBCs was strongly altered by the loss of TRPM1 in the adult retina, with significantly less dendritic and axon terminal labeling in TRPM1 knockout compared to wild type, despite no change in total TPBG detected by immunoblotting. During retinal development, TPBG expression increases dramatically just prior to eye opening with a time course closely correlated with that of TRPM1 expression. In the retina, LRR proteins have been implicated in the development and maintenance of functional bipolar cell synapses, and TPBG may play a similar role in RBCs.
| S-EPMC7255440 | biostudies-literature
Project description:This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes.Newly reported genes for dominant Parkinson's disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder. Mutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson's disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD.
| S-EPMC5522513 | biostudies-other
Project description:Parkinson's disease is the second most prevalent neurodegenerative disorder in the Western world. It is estimated that the neuronal loss related to Parkinson's disease precedes the clinical diagnosis by more than 10 years (prodromal phase) which leads to a subtle decline that translates into non-specific clinical signs and symptoms. By leveraging diffusion magnetic resonance imaging brain (MRI) data evaluated longitudinally, at least at two different time points, we have the opportunity of detecting and measuring brain changes early on in the neurodegenerative process, thereby allowing early detection and monitoring that can enable development and testing of disease modifying therapies. In this study, we were able to define a longitudinal degenerative Parkinson's disease progression pattern using diffusion magnetic resonance imaging connectivity information. Such pattern was discovered using a de novo early Parkinson's disease cohort (n = 21), and a cohort of Controls (n = 30). Afterward, it was tested in a cohort at high risk of being in the Parkinson's disease prodromal phase (n = 16). This progression pattern was numerically quantified with a longitudinal brain connectome progression score. This score is generated by an interpretable machine learning (ML) algorithm trained, with cross-validation, on the longitudinal connectivity information of Parkinson's disease and Control groups computed on a nigrostriatal pathway-specific parcellation atlas. Experiments indicated that the longitudinal brain connectome progression score was able to discriminate between the progression of Parkinson's disease and Control groups with an area under the receiver operating curve of 0.89 [confidence interval (CI): 0.81-0.96] and discriminate the progression of the High Risk Prodromal and Control groups with an area under the curve of 0.76 [CI: 0.66-0.92]. In these same subjects, common motor and cognitive clinical scores used in Parkinson's disease research showed little or no discriminative ability when evaluated longitudinally. Results suggest that it is possible to quantify neurodegenerative patterns of progression in the prodromal phase with longitudinal diffusion magnetic resonance imaging connectivity data and use these image-based patterns as progression markers for neurodegeneration.
| S-EPMC6333847 | biostudies-literature