The Role of Prostaglandin E2 on the Developing Hippocampus - Link to Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, increased repetitive/restricted behaviours and anxiety. The prevalence of autism has been drastically increasing over the past few decades with an associated increase in socioeconomic burden, imposing hardship on many families. Currently, 1 in 66 Canadians are impacted by the disorder and males are four times as likely to be diagnosed with ASD. There is a growing need to understand the underlying mechanisms during development that are contributing to the pathology of ASD in both sexes. Clinical and epidemiological studies suggest exposure to environmental risk factors during pregnancy can impact lipid signaling during development, contributing to the pathology of ASD in children. Previous literature has provided evidence that a bioactive lipid signalling molecule in the brain, known as prostaglandin E2 (PGE2) can be perturbed due to exposure to environmental risk factors during pregnancy, impacting critical processes such as neuronal migration, differentiation and proliferation. Moreover, deficits in hippocampal function are known to contribute to the major symptoms that characterize ASD. In this study, we investigated how prenatal exposure to PGE2 impacts the developing hippocampus in males and females. We examined the effect of PGE2 exposure on dendritic morphology using Golgi-cox staining and proteins that may be driving these morphological changes using western blotting. Our findings suggest that prenatal PGE2 exposure impacts hippocampal dendritic morphology in a sex-dependent manner, which is associated with changes in the expression of proteins involved in cytoskeletal architecture. Ultimately, this study provides us with insight on how perturbed PGE2 signaling impacts cytoskeletal dynamics in the developing hippocampus, contributing to the pathology of autism

The Role of Prostaglandin E2 on the Developing Hippocampus - Link to Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, increased repetitive/restricted behaviours and anxiety. The prevalence of autism has been drastically increasing over the past few decades with an associated increase in socioeconomic burden, imposing hardship on many families. Currently, 1 in 66 Canadians are impacted by the disorder and males are four times as likely to be diagnosed with ASD. There is a growing need to understand the underlying mechanisms during development that are contributing to the pathology of ASD in both sexes. Clinical and epidemiological studies suggest exposure to environmental risk factors during pregnancy can impact lipid signaling during development, contributing to the pathology of ASD in children. Previous literature has provided evidence that a bioactive lipid signalling molecule in the brain, known as prostaglandin E2 (PGE2) can be perturbed due to exposure to environmental risk factors during pregnancy, impacting critical processes such as neuronal migration, differentiation and proliferation. Moreover, deficits in hippocampal function are known to contribute to the major symptoms that characterize ASD. In this study, we investigated how prenatal exposure to PGE2 impacts the developing hippocampus in males and females. We examined the effect of PGE2 exposure on dendritic morphology using Golgi-cox staining and proteins that may be driving these morphological changes using western blotting. Our findings suggest that prenatal PGE2 exposure impacts hippocampal dendritic morphology in a sex-dependent manner, which is associated with changes in the expression of proteins involved in cytoskeletal architecture. Ultimately, this study provides us with insight on how perturbed PGE2 signaling impacts cytoskeletal dynamics in the developing hippocampus, contributing to the pathology of autism

C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two late onset neurodegenerative diseases, have been shown to share overlapping cellular pathologies and genetic origins. Studies suggest that a hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common cause of familial FTD and ALS pathology. The C9orf72 protein is predicted to be a differentially expressed in normal and neoplastic cells domain protein implying that C9orf72 functions as a guanine nucleotide exchange factor (GEF) to regulate specific Rab GTPases. Reported studies thus far point to a putative role for C9orf72 in lysosome biogenesis, vesicular trafficking, autophagy and mechanistic target of rapamycin complex1 (mTORC1) signaling. Here we report the expression, purification and biochemical characterization of C9orf72 protein. We conclusively show that C9orf72 is a GEF. The distinctive presence of both Rab- and Rho-GTPase GEF activities suggests that C9orf72 may function as a dual exchange factor coupling physiological functions such as cytoskeleton modulation and autophagy with endocytosis

Identification of Placenta Growth Factor Determinants for Binding and Activation of Flt-1 Receptor

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The Crystal Structure of Human Placenta Growth Factor-1 (PlGF-1), an Angiogenic Protein, at 2.0 Å Resolution

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Adaptive Copy Number Evolution in Malaria Parasites

Copy number polymorphism (CNP) is ubiquitous in eukaryotic genomes, but the degree to which this reflects the action of positive selection is poorly understood. The first gene in the Plasmodium folate biosynthesis pathway, GTP-cyclohydrolase I (gch1), shows extensive CNP. We provide compelling evidence that gch1 CNP is an adaptive consequence of selection by antifolate drugs, which target enzymes downstream in this pathway. (1) We compared gch1 CNP in parasites from Thailand (strong historical antifolate selection) with those from neighboring Laos (weak antifolate selection). Two percent of chromosomes had amplified copy number in Laos, while 72% carried multiple (2–11) copies in Thailand, and differentiation exceeded that observed at 73 synonymous SNPs. (2) We found five amplicon types containing one to greater than six genes and spanning 1 to >11 kb, consistent with parallel evolution and strong selection for this gene amplification. gch1 was the only gene occurring in all amplicons suggesting that this locus is the target of selection. (3) We observed reduced microsatellite variation and increased linkage disequilibrium (LD) in a 900-kb region flanking gch1 in parasites from Thailand, consistent with rapid recent spread of chromosomes carrying multiple copies of gch1. (4) We found that parasites bearing dhfr-164L, which causes high-level resistance to antifolate drugs, carry significantly (p = 0.00003) higher copy numbers of gch1 than parasites bearing 164I, indicating functional association between genes located on different chromosomes but linked in the same biochemical pathway. These results demonstrate that CNP at gch1 is adaptive and the associations with dhfr-164L strongly suggest a compensatory function. More generally, these data demonstrate how selection affects multiple enzymes in a single biochemical pathway, and suggest that investigation of structural variation may provide a fast-track to locating genes underlying adaptation