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Pre-Clinical Approaches and Methods on Alzheimer’s Disease
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
S. R. Chandra, Pooja Mailankody
The allele of the APOE gene on chromosome 19 is associated with late-onset AD, and genes for sortilin-related receptor 1 (SORL1) and ubiquilin 1 on chromosome 1 are associated with recycling of amyloid precursor peptide (APP). There is overlap of major proteins, like amyloid and tau, in AD, with amyloid and α-synuclein in diffuse Lewy body disease (DLBD) causing problems in specificity. The amyloid hypothesis states that Aβ production and degradation is the pathology common to all types of AD and the causative genes for APP are on chromosome 9. The presenelin-1 gene on chromosome 14 causes severe, very early disease with features of parkinsonism, and is associated with about 60% of inherited AD cases. The presenelin-2 gene on chromosome 1 is a less common cause and is also involved in other diseases. APP is a part of neuronal synapses, and the corresponding gene is located on chromosome 21. Proteolysis of APP by α- or β-secretase leads to secretion of soluble fragments of amyloid alpha or beta peptide. These are subsequently cleaved by γ-secretase to generate either a gamma fragment. In early-onset AD, there is an imbalance between the Aβ42, which increases, and the Aβ40, which decreases, resulting in a propensity for aggregation (Klunk et al. 2004; Kumar et al. 2017). In screening for familial AD cases, it is better to look for presenilin-1 and APP, as they are the most common indicators. APOEε4, located on chromosome 19, is responsible for both familial and sporadic late-onset AD. Other genes which might play a role are ABCA7, CLU, which regulates the clearance of Aβ from the brain, CR1, PLD3, and TREM2, which contribute to chronic inflammation in the brain, and SORL1 and PICALM, which are involved in synaptic connectivity.
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).
SLC2A3 rs12842 polymorphism and risk for Alzheimer’s disease
Published in Neurological Research, 2020
Stylianos Arseniou, Vasileios Siokas, Athina-Maria Aloizou, Polyxeni Stamati, Alexios-Fotios A. Mentis, Zisis Tsouris, Metaxia Dastamani, Eleni Peristeri, Varvara Valotassiou, Dimitrios P. Bogdanos, Georgios M. Hadjigeorgiou, Efthimios Dardiotis
LOAD constitutes up to 95% of AD, and the majority of LOAD cases are sporadic [14]. The APOE gene is the most prevalent genetic risk factor for LOAD and the first confirmed susceptibility gene [13]. The e4 allele is a major risk factor for both EOAD and LOAD, as confirmed by several studies [15]. Genome-wide association studies (GWASs) have identified many other susceptibility genes, as well. These include the following: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, PICALM [7,10,12], CASS4, SLC2A4, ZCWPW1, CELF1, NME8, FERMT2, INPP5D, MEF2 C, SORL1, HLA-DRB5-DRB1, and PTK2B [7]. The majority of these genes are implicated in a specific set of pathways, i.e. cell migration (PTK2B), immune response (INPP5D, MEF2 C), tau pathology (CASS4, FERMT2), and lipid transport and endocytosis (SORL1). Rare variants, such as TREM2 [16], a NOTCH3 mutation [17], MAPT, GRN and variant p.Vall232 Met of the PLD3 gene [13,18,19] have further been identified using Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) studies.
Insights into ultra-low affinity lipase-antibody noncovalent complex binding mechanisms
Published in mAbs, 2022
Elizabeth Sara Hecht, Shrenik Mehta, Aaron T. Wecksler, Ben Aguilar, Nathaniel Swanson, Wilson Phung, Ananya Dubey Kelsoe, W. Henry Benner, Devin Tesar, Robert F. Kelley, Wendy Sandoval, Alavattam Sreedhara
Traditional approaches to detect host cell protein impurities have been hindered by the large dynamic range of co-purified proteins. A variety of sophisticated two-dimensional (2D) techniques, including MS/2D-gel electrophoresis10,37 and 2D-LC-MS,38,39 have proven most successful for detecting new impurities,40 including esterases such as clusterin, PLBL2 and lipoprotein lipase. Yet these techniques cannot explain how HCPs persist into final products. Selection of lipases, and other members of the family of esterases, for targeted analysis could be based on these experimental proteomics datasets41 or the host cell’s protein database (to date, there are 193 results for CHO cell lipases in the TrEMBL database). Based on this approach, two lipases and one esterase (LPLA2, PPT1, and PLD3), previously found as impurities but never shown to bind directly, were tested and revealed in this study to bind by native MS (Figure 2). PPT1 and PLD3 complexes could only be observed in higher ionic strength, suggesting that electrostatic repulsion could play a role in mediating binding. For PPT1, binding was only achieved at a 100:1 protein:mAb solution ratio (Figure 2a), supporting a concentration-dependent binding effect.42 All ratios selected for analysis in this work were chosen to be both compatible with certain bioanalytical assays and to reflect actual relative ratios expected in antibody process purification steps, where antibodies are bound to the column and lipases are 0.5–5% of the flow-through. In all cases, the native solution state of the lipase (monomer or dimer) bound to one antibody.
Molecular mechanisms of ethanol biotransformation: enzymes of oxidative and nonoxidative metabolic pathways in human
Published in Xenobiotica, 2020
Grażyna Kubiak-Tomaszewska, Piotr Tomaszewski, Jan Pachecka, Marta Struga, Wioletta Olejarz, Magdalena Mielczarek-Puta, Grażyna Nowicka
The possibility of phospholipid derivatives (phosphatidylethanol, PEth) formation in the process of phospholipid reesterification, especially phosphatidylcholine, with the participation of phospholipase D (EC 3.1.4.4) is also indicated (Laposata, 1997). In vitro studies indicate that all phospholipase D isoenzymes (PLD1, PLD2, PLD3) are involved in this reaction. Studies conducted by Alling et al., on rats exposed to ethanol intoxication showed the presence of PEth in enterocytes, hepatocytes, kidney and lung cells after as little as two hours after ethanol ingestion. Similar results were obtained in humans. In blood, the maximum concentration of PEth occurs after about 90–120 minutes (Javors et al., 2016), and the presence of PEth can be detected even after 28–30 days of ethanol consumption. The half-life of PEth in blood is about 4–6 days in the absence of ethanol intake after its previous consumption (Hahn et al., 2016). Phosphatidylethanol can also be detected in dried blood samples (Heier et al., 2016). Under physiological pH, PEth occurs in anionic form and constitutes up to 2% of the total membrane pool of phospholipids. In the structure of PEth, there are usually fatty acids with a length of 14–22 carbon atoms and varying degrees of insatiability depending on the type of tissue/organ. Research by Alling et al. and Viel et al. has shown that stearic acid (18:0) and palmitic acid (16:0) are dominant in the liver, oleic acid (18:1) and palmitic acid (16:0) in the brain, and oleic acid (18:1), palmitic acid (16:0) and linoleic acid (18:2) in the blood collected from chronic alcohol users. Phosphatidylethanol influences the stability of biological membranes by increasing their fluidity. Both ionic interactions and formation of hydrogen bonds with PC and PE as well as hydrophobic interactions between PEt ethyl group and PC methyl groups are indicated (Tsujita & Okuda, 1994; Viel et al., 2012; Yu et al., 1996). Moreover, studies conducted on endothelial cell cultures and animals have shown that PEth stimulate angiogenesis by increasing the secretion of the vascular endothelial growth factor (VEGF). This effect is a result of stimulation of MAPK activity by PEth associated with HDL lipoproteins, which transport this lipid from erythrocytes considered as a storehouse of PEth to the endothelium of vessels (Liisanantti et al., 2004). The inhibitory effect of PEth on the activity of membrane ATPase Na+/K+ (Omodeo-Sale et al., 1991) and its stimulating effect on hepatocytic inositol-specific protein kinase C and erythrocytic and hepatic calcium ATPase (Suju et al., 1996) has also been demonstrated. The influence of the described mechanisms on the development of membrane tolerance on ethanol is suggested (Figure 12).