Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific cell types and brain regions. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite appearing normal. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated reduced synthesis of ribosomal and mitochondrial components, 2) glutamatergic neurons showed increased expression of cytoskeletal genes, and 3) GABAergic neurons revealed reduced expression of circadian rhythm genes. These data demonstrate that early translatome responses to neurodegeneration emerge prior to conventional markers of disease and are cell type-specific. Therapeutic strategies may need to target multiple pathways in specific populations of cells, early in disease.     

Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis

Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the {"type":"entrez-geo","attrs":{"text":"GSE16011","term_id":"16011"}}GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis.     

Combination Chemotherapy of BCNU and Didox Acts Synergystically in 9L Glioma Cells

Compounds inhibiting DNA repair and synthesis are expected to act synergistically with BCNU, a standard agent in the therapy of glioblastoma multiforme, and improve survival of patients with malignant gliomas. Ribonucleotide reductase (EC1.17.4.1; RR) catalyzes the rate‐limiting step in DNA synthesis and plays a critical role in maintaining crucial substrates for DNA repair. We have studied the effects of Didox, an inhibitor of RR on 9L glioma cells in combination with BCNU². We analyzed intracellular dNTP pools and found that Didox significantly depleted the intracellular dNTP concentrations. Experiments using cytotoxicity, growth inhibition and clonogenic assays showed significant synergism of Didox and BCNU. Combination regimens using synchronous administration demonstrated highest cytotoxicity. We have also identified altered gene expression in a number of DNA repair related enzymes after BCNU treatment using large‐scale cDNA arrays. The coadministration with Didox could reverse the expression of some of the overexpressed repair gene suggesting possible pathways to circumvent the developing resistance in 9L glioma cells against BCNU. These results introduce the combination of Didox and BCNU as a viable alternative for the treatment of malignant gliomas.     

Control of gene expression in adult skeletal muscle by changes in the inherent level of contractile activity

The evidence presented here supports the concept that multiple, complex controls of gene regulation underlie the adaptive changes in protein quantity associated with alterations of the inherent amount of contractile activity in adult skeletal muscle. Investigations of increased contractile activity by running and resistance exercise, as well by recovery from the reduced contractile activity of limb immobilization suggest that control of the alterations of gene expression are initially (one day) at the level of translation. Likewise, experimental models which do not closely mimic human physical training (i.e. electrical stimulation and chronic overload) produce early alterations in the translational control of gene expression. More prolonged changes in contractile activity, brought about by either physical training or experimental models, produce altered gene expression via changes in pre-, post- and translational control.     

Dysregulated Translation in Neurodevelopmental Disorders: An Overview of Autism‐Risk Genes Involved in Translation

Regulated local translation—whereby specific mRNAs are transported and localized in subcellular domains where they are translated in response to regional signals—allows for remote control of gene expression to concentrate proteins in subcellular compartments. Neurons are highly polarized cells with unique features favoring local control for axonal pathfinding and synaptic plasticity, which are key processes involved in constructing functional circuits in the developing brain. Neurodevelopmental disorders are caused by genetic or environmental factors that disturb the nervous system’s development during prenatal and early childhood periods. The growing list of genetic mutations that affect mRNA translation raises the question of whether aberrant translatomes in individuals with neurodevelopmental disorders share common molecular features underlying their stereotypical phenotypes and, vice versa, cause a certain degree of phenotypic heterogeneity. Here, we briefly give an overview of the role of local translation during neuronal development. We take the autism‐risk gene list and discuss the molecules that (perhaps) are involved in mRNA transport and translation. Both exaggerated and suppressed translation caused by mutations in those genes have been identified or suggested. Finally, we discuss some proof‐of‐principle regimens for use in autism mouse models to correct dysregulated translation.