Multiple Bio-Computational Tools Emerge as Valid Approach in the Assessment of Apolipoproteins Pathogenicity Related Mutations

BioMedInformatics, Journal Year: 2025, Volume and Issue: 5(1), P. 16 - 16

Published: March 20, 2025

Background: Critical studies have unwaveringly established the importance of peculiar single-nucleotide polymorphisms (SNPs) in apolipoproteins (Apos) genes as genetic risk factors for dyslipidemias and their related comorbidities. In this study, we employed silico approaches to analyze mutations Apos. Methods: A comprehensive set computational tools was utilized. The predictions derived from sequence analysis were: SIFT, PolyPhen-2, FATHMM SNPs&GO; structure mCSM, DynaMut2, MAESTROweb, PremPS; prediction pathogenic potential MutPred2, PhD-SNP; profiling aggregation propensity Camsol, Aggrescan3D 2.0, lastly, residual frustration analysis, Frustratometer used. These assess variant effects on protein structure, stability, function. Results: We identified seventeen SNPs total, twelve ApoB, one ApoC2, ApoC3, three ApoE, representing 70%, 6%, 6% 18%, respectively. pathogenity highlighted two rs769452 with amino acid replacement L46P, rs769455 R163C. aggregation/solubility revealed that L46P leads a decrease ApoE aggregation. R163C, showed solubility used, resulting destabilizing altering its solubility. Conclusions: studied methodologies clinically significant variants, highlighting robustness integrated approach. future direction research is create multiplex panel here APOE expanding other proteins assessment disease which correlates.

Language: Английский

Differences in transcriptome characteristics and drug repositioning of Alzheimer's disease according to sex

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106909 - 106909

Published: April 1, 2025

Previous studies have shown significant sex differences in AD with regarding its epidemiology, pathophysiology, clinical presentation, and treatment response. However, the transcriptome variances associated remain unclear. RNA sequencing (RNA-seq) transcriptomic analyses were performed on peripheral blood samples from total of 54 patients, including male patients (n = 15), female 10), MCI 7), 11), healthy controls 6), 5). The snRNA-seq dataset (GSE167494, GSE157827) prefrontal cortex tissues was obtained Gene Expression Omnibus (GEO). We conducted an investigation into differentially expressed genes pathways cells as well both consideration to sex-related factors. Additionally, we analyzed distribution characteristics cerebral interaction communication between patients. Connectivity Map (CMap) utilized for predicting screening potential sex-specific drugs AD. profile biological processes exhibit discernible differences, upregulation BASP1 arousing TNS1 various cell types differs like neuron oligodendrocyte decreased endothelial astrocyte increased compared male, while a multitude differential expression. results analysis, such collagen signaling pathway, suggest that disparities impact intercellular interactions within among individuals By drug repositioning, several drugs, torin-2 YM-298198, might therapeutic value or AD, homoharringtonine teniposide opposite effects different sexes. single-cell which providing basis future stratified

Language: Английский

Focused Ultrasound-Mediated Disruption of the Blood–Brain Barrier for AAV9 Delivery in a Mouse Model of Huntington’s Disease

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(6), P. 710 - 710

Published: May 24, 2024

Huntington’s disease (HD) is a monogenic neurodegenerative disorder caused by cytosine–adenine–guanine (CAG) trinucleotide repeat expansion in the HTT gene. There are no cures for HD, but genetic basis of this makes gene therapy viable approach. Adeno-associated virus (AAV)-miRNA-based therapies have been demonstrated to be effective lowering mRNA; however, blood–brain barrier (BBB) poses significant challenge delivery brain. Delivery strategies include direct injections into central nervous system, which invasive and can result poor diffusion viral particles through brain parenchyma. Focused ultrasound (FUS) an alternative approach that used non-invasively deliver AAVs temporarily disrupting BBB. Here, we investigate FUS-mediated single-stranded AAV9 bearing cDNA GFP 2-month-old wild-type mice zQ175 HD mouse model at 2-, 6-, 12-months. FUS treatment improved all groups. The efficacy was similar WT groups, with exception 12-month cohort, where observed decreased expression. Astrocytosis did not increase after treatment, even within group exhibiting higher baseline levels GFAP These findings demonstrate AAV9-based targeted regions disease.

Language: Английский