Biology subjects

Zaman, T.

Publications and source records attributed to Zaman, T..

4 recordsLinked to original sources

bioRxiv2024

Modulation of Purkinje Cell Inhibition by Stem Cell Factor

Abstract / SummaryTarget derived factors influence the specification, maintenance, and modulation of synaptic connectivity. The transmembrane protein, Kit Ligand, and Kit receptor tyrosine kinase are differentially expressed in connected neurons. In development and postnatal periods, these proteins maintain connectivity between cerebellar Purkinje cells (PC) that express Kit Ligand, and presynaptic Molecular Layer Interneurons (MLI) expressing Kit. In this study, it is demonstrated that Stem Cell Factor (SCF), the active extracellular domain of Kit Ligand, produces a potent potentiation of inhibition upon Purkinje Cells. The SCF enhancement of inhibition required presynaptic Kit, produced long term suppression of PC firing, and was associated with a specific potentiation of basket cells of the MLI1 subtype. It is posited that SCF exerts a postsynaptic effect involving enhanced sensitivity of somatic PC GABAA receptors. This work demonstrates that the SCF/Kit axis modulates synaptic function in adult tissue.

neuroscience↗

bioRxiv2023

Kit Ligand and Kit receptor tyrosine kinase sustain synaptic inhibition of Purkinje Cells

The cell-type specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/542885v2_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1d53d9eorg.highwire.dtl.DTLVardef@c05c4borg.highwire.dtl.DTLVardef@eb58eeorg.highwire.dtl.DTLVardef@11b8431_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs

RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. While the role of RAS/MAPK genes have been well studied in cancer, less is known about their function during neurodevelopment. There are many genes that work in concert to regulate RAS/MAPK signaling, suggesting that if common brain phenotypes could be discovered they could have a broad impact on the many other disorders caused by distinct RAS/MAPK genes. We assessed the cellular and molecular consequences of hyperactivating the RAS/MAPK pathway using two distinct genes in a cell type previously implicated in RAS/MAPK-mediated cognitive changes, cortical GABAergic interneurons. We uncovered some GABAergic core programs that are commonly altered in each of the mutants. Notably, hyperactive RAS/MAPK mutants bias developing cortical interneurons towards those that are somatostatin+. The increase in somatostatin+ interneurons could also be induced by elevated neural activity and we show the core RAS/MAPK signaling pathway is one mechanism by which this occurs. Overall, these findings present new insights into how different RAS/MAPK mutations can converge on GABAergic interneurons, which may be important for other RAS/MAPK genes/disorders.

neuroscience↗

bioRxiv2018

Blood-based molecular biomarker signatures in Alzheimer’s disease: Insights from systems biomedicine analyses

Background and objectivesAlzheimers disease (AD) is the progressive neurodegenerative disease characterized by dementia, but no peripheral biomarkers available yet that can detect the AD. This study aimed to identify systems biomarker signatures in the AD through integrative analyses.\n\nMaterials and MethodsWe used two microarray transcriptomics datasets of blood from AD patients to identify differentially expressed genes (DEGs). Geneset and protein overrepresentation analysis, protein-protein interaction (PPI), DEGs-Transcription Factor interactions, DEGs-MicroRNAs interactions, protein-drug interactions, and protein subcellular localizations analyses were done on common DEGs.\n\nResultsTotal 25 DEGs were detected between the two datasets. Integration of DEGs with biomolecular networks revealed hub proteins (TUBB, ATF3, NOL6, UQCRC1, SND1, CASP2, BTF3, INPP5K, VCAM1, and CSTF1), TFs (FOXC1, ZNF3, GEMIN7, and SMG9), miRNAs (mir-20a-5p, mir-93-5p, mir-16-5p, let-7b-5p, mir-708-5p, mir-24-3p, mir-26b-5p, mir-17-5p, mir-4270, and mir-4441). The analyses revealed candidate blood based biomarkers in the AD. We evaluated the histone modifications of the identified biomolecules. The hub genes and transcription factors (TFs) revealed that they possess several histone modification sites associated with Alzheimers disease. The protein-drug interactions revealed 10 candidate drugs consisting of antineoplastic (Vinorelbine, Vincristine, Vinblastine, Epothilone D, Epothilone B, CYT997, and ZEN-012), dermatologicals (Podofilox), and immunosuppressive agents (Colchicine) that may target the candidate systems biomarkers. The subcellular localization analysis revealed the interactions of the DEGs range from nucleus to plasma membrane through cytosol.\n\nConclusionsThis study presents blood based systems molecular biomarker signatures at RNA and protein levels which might be useful as peripheral biomarkers in the AD. The candidate drugs, histone modification sites, and subcellular localizations will be useful in future drug design in the AD.

systems biology↗