Chen-Plotkin, A. S. et al. Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration. Hum. Mol. Genet. 17, 1349-1362

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2008; 17(10):1349-62. DOI: 10.1093/hmg/ddn023
Source: PubMed


Frontotemporal lobar degeneration is a fatal neurodegenerative disease that results in progressive decline in behavior, executive function and sometimes language. Disease mechanisms remain poorly understood. Recently, however, the DNA- and RNA-binding protein TDP-43 has been identified as the major protein present in the hallmark inclusion bodies of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), suggesting a role for transcriptional dysregulation in FTLD-U pathophysiology. Using the Affymetrix U133A microarray platform, we profiled global gene expression in both histopathologically affected and unaffected areas of human FTLD-U brains. We then characterized differential gene expression with biological pathway analyses, cluster and principal component analyses, and subgroup analyses based on brain region and progranulin (GRN) gene status. Comparing 17 FTLD-U brains to 11 controls, we identified 414 upregulated and 210 downregulated genes in frontal cortex (P-value < 0.001). Moreover, cluster and principal component analyses revealed that samples with mutations or possibly pathogenic variations in the GRN gene (GRN+, 7/17) had an expression signature that was distinct from both normal controls and FTLD-U samples lacking GRN gene variations (GRN-, 10/17). Within the subgroup of GRN+ FTLD-U, we found >1300 dysregulated genes in frontal cortex (P-value < 0.001), many participating in pathways uniquely dysregulated in the GRN+ cases. Our findings demonstrate a distinct molecular phenotype for GRN+ FTLD-U, not readily apparent on clinical or histopathological examination, suggesting distinct pathophysiological mechanisms for GRN+ and GRN- subtypes of FTLD-U. In addition, these data from a large number of human brains provide a valuable resource for future testing of disease hypotheses.

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    • "The most of the dysregulated pathways, as the MPAK signalling pathway, the calcium signalling pathway, the gap junction and the ECM-receptor interaction, confirm the analysis of [35]. The dysregulated pathways with a significant p-PERT were the glutamatergic synapse and GABAergic synapse. "
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    ABSTRACT: Background It is currently accepted that the perturbation of complex intracellular networks, rather than the dysregulation of a single gene, is the basis for phenotypical diversity. High-throughput gene expression data allow to investigate changes in gene expression profiles among different conditions. Recently, many efforts have been made to individuate which biological pathways are perturbed, given a list of differentially expressed genes (DEGs). In order to understand these mechanisms, it is necessary to unveil the variation of genes in relation to each other, considering the different phenotypes. In this paper, we illustrate a pipeline, based on Structural Equation Modeling (SEM) that allowed to investigate pathway modules, considering not only deregulated genes but also the connections between the perturbed ones. Results The procedure was tested on microarray experiments relative to two neurological diseases: frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) and multiple sclerosis (MS). Starting from DEGs and dysregulated biological pathways, a model for each pathway was generated using databases information biological databases, in order to design how DEGs were connected in a causal structure. Successively, SEM analysis proved if pathways differ globally, between groups, and for specific path relationships. The results confirmed the importance of certain genes in the analyzed diseases, and unveiled which connections are modified among them. Conclusions We propose a framework to perform differential gene expression analysis on microarray data based on SEM, which is able to: 1) find relevant genes and perturbed biological pathways, investigating putative sub-pathway models based on the concept of disease module; 2) test and improve the generated models; 3) detect a differential expression level of one gene, and differential connection between two genes. This could shed light, not only on the mechanisms affecting variations in gene expression, but also on the causes of gene-gene relationship modifications in diseased phenotypes.
    BMC Bioinformatics 05/2014; 15(1):132. DOI:10.1186/1471-2105-15-132 · 2.58 Impact Factor
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    • "Moreover, GRN (−) FTLD-TDP cases with similar patterns of TDP-43 pathology did not demonstrate TMEM106B expression extending into neuronal processes, suggesting that this effect is specific to the GRN (+) FTLD-TDP genetic subtype. We have previously shown that GRN (+) FTLD-TDP has a distinct global mRNA expression profile [32], suggesting that distinct pathophysiological mechanisms may exist in this molecularly defined subgroup. Moreover, recent evidence implicates TMEM106B in GRN (+) FTLD-TDP pathways. "
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    ABSTRACT: Background Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP. Moreover, a recent genome-wide association study (GWAS) identified multiple SNPs within the uncharacterized gene TMEM106B that significantly associated with FTLD-TDP, suggesting that TMEM106B genotype confers risk for FTLD-TDP. Indeed, TMEM106B expression levels, which correlate with TMEM106B genotype, may play a role in the pathogenesis of disease. Results Since little is known about TMEM106B and its expression in human brain, we performed immunohistochemical studies of TMEM106B in postmortem human brain samples from normal individuals, FTLD-TDP individuals with and without GRN mutations, and individuals with other neurodegenerative diseases. We find that TMEM106B protein is cytoplasmically expressed in both histopathologically affected and unaffected areas of the brain by neurons, glia, and endothelial cells/pericytes. Furthermore, we demonstrate that TMEM106B expression may differ among neuronal subtypes. Finally, we show that TMEM106B neuronal expression is significantly more disorganized in FTLD-TDP cases with GRN mutations, compared to normal and disease controls, including FTLD-TDP cases without GRN mutations. Conclusions Our data provide an initial neuropathological characterization of the newly discovered FTLD-TDP-associated protein TMEM106B. In addition, we demonstrate that FTLD-TDP cases with GRN mutations exhibit a loss of neuronal TMEM106B subcellular localization, adding to evidence that TMEM106B and progranulin may be pathophysiologically linked in FTLD-TDP.
    07/2013; 1(1). DOI:10.1186/2051-5960-1-36
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    • "Beside their intrinsic worth in terms of gene expression analysis, one of the most interesting aspects of gathering several data sets is represented by the possibility to compare them with each other, in order to determine if there are common themes/genes. Most of all, it would also be interesting to compare these results with similar microarray-based studies that have been performed on the brain of individuals affected by ALS or FTLD (Baciu et al., 2012; Chen-Plotkin et al., 2008; Kocerha et al., 2011; Mishra et al., 2007; Rabin et al., 2010). Before we discuss these comparisons, however, it is important to provide some background on the microarray technique itself. "
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    ABSTRACT: Dysfunctions in RNA processing and in particular the aberrant regulation of RNA binding proteins (RBPs) have recently been shown to play a fundamental role in the pathogenesis of neurodegenerative diseases. Understanding the pathogenic mechanisms involved will require the elucidation of the role(s) played by these RBPs in the general cell metabolism and neuronal survival in particular. In the past, the preferred approach has been to determine first of all the functional properties of the factor(s) of interest and then use of this knowledge to determine targets in biologically relevant events. More recently, novel experimental approaches such as microarrays, RNA-seq and CLIP-seq have also become very popular to study RBPs. The advantage of these approaches, collectively known as High Throughput Screening (HTS), is their ability to determine gene expression changes or RNA/protein targets at a global cellular level. In theory, HTS strategies should be ideal for uncovering novel functional roles/targets of any RBP inside the cell. In practice, however, there are still difficulties in getting a coherent picture from all the huge amount of data they generate, frequently not validated experimentally and thus of unknown value. They may even act unfavorably towards a specific increase of knowledge of RBP functions, as the incomplete results are taken as solid data. In this work we will illustrate as an example the use of the HTS methodologies to characterize the interactions of a specific RNA binding protein: TDP-43. The multiple functions of this protein in RNA processing and its involvement in the pathogenesis of several forms of ALS, FTLD and other neurodegenerative diseases make it an excellent substrate for our analysis of the various advantages and limitations of different HTS experimental approaches.
    Molecular and Cellular Neuroscience 03/2013; 56. DOI:10.1016/j.mcn.2013.03.001 · 3.84 Impact Factor
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