Biology subjects

Haque, Z.

Publications and source records attributed to Haque, Z..

4 recordsLinked to original sources

bioRxiv2025

Mapping the microRNA-mediated crosstalk between insulin resistance and Alzheimers disease : a computational genomic insight

Insulin resistance (IR) and Alzheimers disease (AD) share overlapping molecular mechanisms, but the precise link between these conditions remains unclear. MicroRNAs, as post-transcriptional regulators of gene expression, may mediate this connection by targeting genes involved in both pathways. In this study, we employed a multi-step bioinformatics approach to identify microRNAs that simultaneously regulate genes associated with IR and AD. Twenty key IR-related genes were selected from the literature, and their microRNA regulators were predicted using five computational tools. These predictions were validated using experimentally supported databases (TarBase and miRTarBase), and each miRNA-gene interaction was scored. Sixteen high-confidence microRNAs were shortlisted based on cumulative prediction and validation scores. These microRNAs were then analyzed for their interactions with AD pathway genes via KEGG pathway analysis. The AD-related target genes were further processed through protein-protein interaction network analysis using STRING and hub gene identification via Cytoscape. Functional enrichment of these hub genes using Gene Ontology and KEGG analysis revealed their involvement in shared biological processes, including apoptosis, insulin signaling, glucose metabolism, and neuroinflammation. Prominent candidates such as miR-7-5p, miR-106b, miR-424-5p, and miR-15a were identified. These results suggest that a subset of microRNAs may serve as critical molecular links between IR and AD, offering potential targets for early diagnosis and intervention.

neuroscience↗

bioRxiv2022

ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventative or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimers disease, ALS, Parkinsons disease, and Huntingtons disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.

neuroscience↗

bioRxiv2021

Impaired oligodendrocyte maturation is an early feature in SCA3 disease pathogenesis

Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, is a polyglutamine neurodegenerative disease for which there is no disease-modifying therapy. The polyglutamine-encoding CAG repeat expansion in the ATXN3 gene results in expression of a mutant form of the ATXN3 protein, a deubiquitinase that causes selective neurodegeneration despite being widely expressed. The mechanisms driving neurodegeneration in SCA3 are unclear. Research to date, however, has focused almost exclusively on neurons. Here, using equal male and female age-matched transgenic mice expressing full-length human mutant ATXN3, we identified early and robust transcriptional changes in selectively vulnerable brain regions that implicate oligodendrocytes in disease pathogenesis. We mapped transcriptional changes across early, mid, and late stages of disease in two selectively vulnerable brain regions, the cerebellum and brainstem. The most significant disease-associated module through weighted gene co-expression network analysis revealed dysfunction in SCA3 oligodendrocyte maturation. These results reflect a toxic gain of function mechanism, as ATXN3 knockout mice do not exhibit any impairments in oligodendrocyte maturation. Genetic crosses to reporter mice revealed a marked reduction in mature oligodendrocytes in SCA3-disease vulnerable brain regions and ultrastructural microscopy confirmed abnormalities in axonal myelination. Further study of isolated oligodendrocyte precursor cells from SCA3 mice established that this impairment in oligodendrocyte maturation is a cell autonomous process. We conclude that SCA3 is not simply a disease of neurons and the search for therapeutic strategies and disease biomarkers will need to account for non-neuronal involvement in SCA3 pathogenesis. SIGNIFICANCE STATEMENTDespite advances in SCA3 disease understanding, much remains unknown about how the disease gene causes brain dysfunction ultimately leading to cell death. We completed a longitudinal transcriptomic analysis of vulnerable brain regions in SCA3 mice to define the earliest and most robust changes across disease progression. Through gene network analyses followed up with biochemical and histological studies in SCA3 mice, we provide evidence for severe dysfunction in oligodendrocyte maturation early in SCA3 pathogenesis. Our results advance understanding of SCA3 disease mechanisms, identify additional routes for therapeutic intervention, and may provide broader insight into polyglutamine diseases beyond SCA3.

neuroscience↗

bioRxiv2019

Immunoinformatic and dynamic simulation-based designing of a multi-epitope vaccine against emerging pathogen Elizabethkingia anophelis

Elizabethkingia anophelis is an emerging human pathogen causing neonatal meningitis, catheter-associated infections and nosocomial outbreaks with high mortality rates. Besides, they are resistant to most antibiotics used in empirical therapy. In this study, therefore, we used immunoinformatic approaches to design an epitope-based vaccine against E. anophelis as an alternative preventive measure. Initially, T-cell (CTL and HTL) and B-cell (LBL) epitopes were predicted from the highest antigenic protein. The CTL and HTL epitopes together had a population coverage of 99.97% around the world. Eventually, 6 CTL, 7 HTL, and 2 LBL epitopes were selected and used to construct a multiepitope vaccine. The vaccine protein was found to be highly immunogenic, non-allergenic, and non-toxic. Codon adaptation and in silico cloning were performed to ensure better expression within E. coli K12 host system. The stability of the vaccine structure was also improved by disulphide bridging. In addition, molecular docking and dynamic simulation revealed good and stable binding affinity between the vaccine and receptor. The immune simulation showed higher levels of T-cell and B-cell activities which was in coherence with actual immune response. Repeated exposure simulation resulted in higher clonal selection and faster antigen clearance. Nevertheless, experimental validation is required to ensure the immunogenic potency and safety of this vaccine to control E. anophelis infection in the future.

bioinformatics↗