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Insulin Resistance as a Risk Factor for Alzheimer's Disease
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Miren Ettcheto, Amanda Cano, Elena Sanchez-Lopez, Carme Auladell, Jaume Folch, Antoni Camins
In this context, Grillo and colleagues performed a preclinical study in a selective IR model of the rat using a lentiviral vector expressing an insulin receptor antisense sequence (42). They demonstrated that the generation of specific IR in the hippocampus affected the synaptic plasticity in this area by regulating the expression and trafficking of the glutamate receptor. Specifically, this study showed that IR decreased the phosphorylation of the serine 845 residue of the glutamate receptor 1 (GluA1) and the expression of glutamate ionotropic receptor N-Methyl D-Aspartate (NMDA) type subunit 2B (GluN2B), which are directly involved in long term potentiation (LTP) (42, 43). In line with these results, it has been reported that insulin administration promotes dendritic spine formation in primary cultures of rat hippocampal neurons and improves synaptic transmission through NMDA receptor (glutamatergic transmission) in the hippocampus, modulating the surface expression of these receptors and stimulating the phosphorylation of GluN2A and GluN2B subunits (36, 44).
Central nervous system: Paediatric and neurodevelopmental disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
A persisting and severe epileptic encephalopathy may have many different causes. Among those with an underlying genetic basis, there is a wide range of genes that can be involved. There are two X-chromosome genes to mention, ARX and CDKL5, and three autosomal dominant genes, SCN1A, STXBP1 and GRIN2A, to single out as especially important. The phenotypes associated with SCN1A constitute a wide range of clinical disorders, from ‘benign’ febrile seizures in young children, often familial, to Dravet syndrome, that often begins with severe febrile seizures at ∼6 months and then leads into a severe lifelong epilepsy disorder that changes in character, is difficult to treat and is not usually passed to children because patients are unlikely to reproduce. Also difficult to treat is the lifelong epileptic disorder that can result from mutations in CDKL5, most often affecting girls and often also causing microcephaly, autism and spasticity and sharing some behavioural features with Rett syndrome. ARX mutations will often cause infantile spasms, like CDKL5 mutations, and are also known as a cause of lissencephaly. Pathogenic variants in STXBP1 are an important cause of the Ohtahara syndrome. Different mutations in GRIN2A may have different effects on the function of the NMDA receptor and may respond best to different treatments. The potential for such a rational approach to therapeutics is one of the eagerly anticipated benefits of molecular precision diagnostics in the channelopathies. However, this will not be as straightforward as ‘one drug for (seizures caused by) one gene’.
Precision medicine in stroke and other related neurological diseases
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Anjana Munshi, Vandana Sharma, Sulena Singh
The understanding of mechanisms of neuronal alteration and maintenance of their molecular signatures during disease progression is a major requirement for clinically correct diagnosis of neurological disease. Numerous diagnostic investigations, including imaging techniques, are opted by concerned clinicians for prediction and analysis of the disease. Apart from these diagnostic measures, genomic profiling is one of the cornerstones of precision or personalized therapy, which not only forecasts the susceptibility to disease but also predicts the best possible treatment for the individual patient. Many genes, including ATP binding cassette subfamily A member 7 (ABCA7), bridging integrator 1 (BIN1), complement receptor 1 (CR1), phospholipase D3 gene (PLD3), and phosphatidylinositol-binding clathrin assembly protein gene (PICALM), have been revealed to contribute toward the excess burden of deleterious coding mutations in Alzheimer's disease (Ma et al., 2014; Jiang et al., 2014; Tan et al., 2014b; Cacace et al., 2015; Vardarajan et al., 2015). In the epileptic encephalopathies, trio exome sequencing has identified that genes UDP-N-acetylglucosaminyltransferase subunit (ALG), gamma-aminobutyric acid type a receptor β3 gene (GABRB3), dynamin 1 (DNM1), hyperpolarization activated cyclic nucleotide gated potassium channel 1 (HCN1), glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), gamma-aminobutyric acid type A receptor alpha1 subunit (GABRA1), G protein subunit alpha O1 (GNAO1), potassium sodium-activated channel subfamily T member 1 (KCNT1), sodium voltage-gated channel alpha subunit 2 (SCN2A), sodium voltage-gated channel alpha subunit 8 (SCN8A), and solute carrier family 35 member A2 (SLC35A2) are associated with epileptogenesis. Many of the proteins encoded by these genes have been found to be associated with synaptic transmission (Epi, 2015).
Advances in genetic testing and optimization of clinical management in children and adults with epilepsy
Published in Expert Review of Neurotherapeutics, 2020
Marcello Scala, Amedeo Bianchi, Francesca Bisulli, Antonietta Coppola, Maurizio Elia, Marina Trivisano, Dario Pruna, Tommaso Pippucci, Laura Canafoglia, Simona Lattanzi, Silvana Franceschetti, Carlo Nobile, Antonio Gambardella, Roberto Michelucci, Federico Zara, Pasquale Striano
The type of the genetic variant identified in a specific gene further influences the therapeutic strategy. As an example, the administration of the appropriate treatment in patients with de novo mutation in GRIN2A, encoding the N-methyl-D-aspartate (NMDA) receptor subunit NR2A, strongly depends on the functional effect of the mutation [148]. Indeed, drugs with NMDA-blocking activity (e.g., memantine and felbamate) have shown to be effective in reducing the frequency and severity of seizures in individuals carrying gain-of-function variants and new drugs which selectively block NMDA receptors containing the NR2A subunit are being developed (e.g., MPX-004 and MPX-007) [149–151]. However, the picture may be more complex in case of variants affecting the sensitivity of the NMDA receptor to these drugs [152]. Subjects harboring loss-of-function GRIN2A variants may instead benefit from treatment with positive allosteric modulators of NMDA receptors [153–155].
Convergent functional genomics of cocaine misuse in humans and animal models
Published in The American Journal of Drug and Alcohol Abuse, 2020
Diego A. Forero, Yeimy González-Giraldo
We provide a list of 33 DE genes identified in a meta-analysis of mouse models of cocaine exposure and a list of 99 top genes identified in a CFG analysis of cocaine use in humans and mouse and rat models. Several of these genes, such as GRIN2A and GRIN2B, are known to have a key role in brain function and plasticity, which is in agreement with the hypothesis of a dysfunction of synaptic plasticity in addiction mechanisms (47–51). These CFG-derived genes are interesting candidates to analyze in future studies of cocaine misuse. It is possible that the low number of available studies with raw data and their heterogeneity, in terms of platforms and regions, might explain the lack of significant DE genes in the meta-analyses for GWES in humans and rats.
Interleukin-10 restores glutamate receptor-mediated Ca2+-signaling in brain circuits under loss of Sip1 transcription factor
Published in International Journal of Neuroscience, 2021
Maria V. Turovskaya, Ekaterina A. Epifanova, Victor S. Tarabykin, Alexei A. Babaev, Egor A. Turovsky
Chronic actions of active compounds recorded by changes in cell activity [29] are undoubtedly associated with changes in the level of gene expression. A comparative analysis of PCR data showed that the reduced Ca2+ signals of Sip1fl/fl neurons grown under standard conditions to activation of NMDA, AMPA, and kainate receptors by selective agonists and coincide with the suppressed expression level of the genes encoding the subunits forming these receptors (Figure 2(D), Sip1fl/fl) in comparison with wild-type cortical neurons (Figure 2(D), WT). The expression levels of Grin2a and Grin2b genes encoding the NR2A and NR2B subunits of the NMDA receptors, Gria1 and Gria2, encoding the GluA1 and GluA2 subunits of the AMPA receptors are reduced by more than 3–4.5 and 2.5–3 times, respectively (Figure 2(D)). As for kainate receptors, it was shown a 4-fold decrease in expression of Grik2 gene which encodes the kainate type subunit 2 KAR while the expression level of Grik1 (glutamate ionotropic receptor kainate type subunit 1) does not change during Sip1 mutation (Figure 2(D)). At the same time, in cells grown in the presence of 1 nM IL-10 the expression of the Grin2a and Grin2b genes increases by 42.6% (Figure 2(D), Sip1fl/fl + IL-10 group). The expression level of the Gria1 gene does not change in the Sip1fl/fl + IL-10 group but the expression of Gria2 increases by 36% in comparison with cells of Sip1 homozygotes grown under standard conditions. As for the kainate receptor subunits in the Sip1fl/fl + IL-10 group a significant increase in their expression occurs due to the Grik2 gene whereas the Grik1 level does not change (Figure 2(D)).