study-functions-activities-neuronal-k-cl-co-transporter-kcc2-using

Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting

Potassium chloride cotransporters 2 (KCC2) is a member of the solute carrier family 12 (SLC12) of cation-chloride-cotransporters (CCCs), found exclusively ...

University of Exeter, Hatherly Laboratories

Morphological screening of mouse brains with known behavioral deficits can give great insight into the relationship between brain regions and their behavior. Oxytocin- and CD38-deficient mice have previously been shown to have behavioral phenotypes, such as restrictions in social memory, social interactions, and maternal behavior. CD38 is reported as an autism spectrum disorder (ASD) candidate gene and its behavioral phenotypes may be linked to ASD. To address whether these behavioral phenotypes relate to brain pathology and neuronal morphology, here we investigate the morphological changes in the CD38-deficient mice brains, with focus on the pathology and neuronal morphology of the cortex and hippocampus, using Nissl staining, immunohistochemistry, and Golgi staining. No difference was found in terms of cortical layer thickness. However, we found abnormalities in the number of neurons and neuronal morphology in the visual cortex and dentate gyrus (DG). In particular, there were arborisation differences between CD38 and CD38 mice in the apical dendrites of the visual cortex and hippocampal CA1 pyramidal neurons. The data suggest that CD38 is implicated in appropriate development of brain regions important for social behavior.

CD38 is Required for Dendritic Organization in Visual Cortex and Hippocampus.

Alzheimer's disease (AD) is a debilitating disease and the most common cause of dementia. As the world population ages even modest advances in therapies and preventative strategies would be of benefit. The specific physiological function of the amyloid precursor protein (APP) remains unclear despite strong genetic and biochemical evidence of APP involvement in AD. The intricate molecular processes of the nervous system rely on interactions between cell surface receptors coupled to intracellular downstream signaling networks. APP is an integral membrane protein which interacts with members of the Contactin family of proteins. Here we review recent progresses in the field and discuss the physiological importance of APP-Contactin interaction, as well as their roles and contributions in the pathophysiology of AD.

The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer's Disease.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

Article	Year
CD38 is Required for Dendritic Organization in Visual Cortex and Hippocampus. Neuroscience\| PubMed ID: 29306053	2018
The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer's Disease. Neuroscience\| PubMed ID: 31705890	2020
Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies. American journal of human genetics\| PubMed ID: 36055212	2022

Asami Oguro-Ando

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