Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases

<p>Abstract</p> <p>Background</p> <p>The neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for <it>Cln1 </it>and <it>Cln5</it>. Both mouse-models replicate the NCL phenotype and neuropathology; the <it>Cln1-/- </it>model presents with early onset, severe neurodegenerative disease, whereas the <it>Cln5-/- </it>model produces a milder disease with a later onset.</p> <p>Results</p> <p>Here we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old <it>Cln1-/- </it>and <it>Cln5-/- mice</it>. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. We analyzed locus specific gene expression and showed regional clustering of <it>Cln1 </it>and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products; adenylate cyclase-associated protein 1 (Cap1), protein tyrosine phosphatase receptor type F (Ptprf) and protein tyrosine phosphatase 4a2 (Ptp4a2). The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of <it>Cln1-/- </it>and <it>Cln5-/- </it>cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and β-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3.</p> <p>Conclusion</p> <p>Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since <it>CLN1 </it>and <it>CLN5 </it>code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.</p

Pathways affected by asbestos exposure in normal and tumour tissue of lung cancer patients

<p>Abstract</p> <p>Background</p> <p>Studies on asbestos-induced tumourigenesis have indicated the role of, e.g., reactive oxygen/nitrogen species, mitochondria, as well as NF-κB and MAPK signalling pathways. The exact molecular mechanisms contributing to asbestos-mediated carcinogenesis are, however, still to be characterized.</p> <p>Methods</p> <p>In this study, gene expression data analyses together with gene annotation data from the Gene Ontology (GO) database were utilized to identify pathways that are differentially regulated in lung and tumour tissues between asbestos-exposed and non-exposed lung cancer patients. Differentially regulated pathways were identified from gene expression data from 14 asbestos-exposed and 14 non-exposed lung cancer patients using custom-made software and Iterative Group Analysis (iGA). Western blotting was used to further characterize the findings, specifically to determine the protein levels of UBA1 and UBA7.</p> <p>Results</p> <p>Differences between asbestos-related and non-related lung tumours were detected in pathways associated with, e.g., ion transport, NF-κB signalling, DNA repair, as well as spliceosome and nucleosome complexes. A notable fraction of the pathways down-regulated in both normal and tumour tissue of the asbestos-exposed patients were related to protein ubiquitination, a versatile process regulating, for instance, DNA repair, cell cycle, and apoptosis, and thus being also a significant contributor of carcinogenesis. Even though UBA1 or UBA7, the early enzymes involved in protein ubiquitination and ubiquitin-like regulation of target proteins, did not underlie the exposure-related deregulation of ubiquitination, a difference was detected in the UBA1 and UBA7 levels between squamous cell carcinomas and respective normal lung tissue (p = 0.02 and p = 0.01) without regard to exposure status.</p> <p>Conclusion</p> <p>Our results indicate alterations in protein ubiquitination related both to cancer type and asbestos. We present for the first time pathway analysis results on asbestos-associated lung cancer, providing important insight into the most relevant targets for future research.</p

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD