Biology subjects

Bose, C.

Publications and source records attributed to Bose, C..

3 recordsLinked to original sources

bioRxiv2021

Synaptosome microRNAs regulate synapse functions in Alzheimer's disease

MicroRNAs (miRNAs) are found in nerve terminals, synaptic vesicles, and synaptosomes, but it is unclear whether synaptic and cytosolic miRNA populations differ in Alzheimers disease (AD) or if synaptosomal miRNAs affect AD synapse activity. To address these questions, we generated synaptosomes and cytosolic fractions from postmortem brains of AD and unaffected control (UC) samples and analyzed them using a global Affymetrix miRNAs microarray platform. A group of miRNAs significantly differed (p<0.0001) with high fold changes variance (+/- >200-fold) in their expressions in different comparisons- 1) UC synaptosome vs UC cytosol, 2) AD synaptosomes vs AD cytosol, 3) AD cytosol vs UC cytosol, and 4) AD synaptosomes vs UC synaptosomes. MiRNAs data analysis revealed that some potential miRNAs were consistently different across sample groups. These differentially expressed miRNAs were further validated using AD postmortem brains, brains of APP transgenic (Tg2576), Tau transgenic (P301L), and wild type mice. The miR-501-3p, miR-502-3p and miR-877-5p were identified as potential synaptosomal miRNAs upregulated with disease progression based on AD Braak stages. Gene Ontology Enrichment and Ingenuity Pathway Analysis of synaptosomal miRNAs showed the involvement of miRNAs in nervous system development, cell junction organization, synapse assembly formation, and function of GABAergic synapse. This is the first description of synaptic versus cytosolic miRNAs in AD and their significance in synapse function.

neuroscience↗

bioRxiv2021

Role of RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease

The purpose of our study is to understand the role of the Ralbp1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimers disease (AD) pathogenesis. The Ralbp1 gene encodes the 76 kDa protein Rlip (aka RLIP76). Previous studies have revealed its role in OS-related cancer. However, Rlip is transcriptionally regulated by EP300, a CREB-binding protein that is important for synaptic plasticity in the brain. Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. OS causes rapid cellular accumulation of Rlip and its translocation from a tubulin-bound complex to the plasma membrane, mitochondria and nucleus. Therefore, Rlip may play an important role in maintaining cognitive function in the face of OS-related injury. This study is aimed to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype and Rlip+/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in mouse brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, inhibition of stress-activated gene expression, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues of these mice. Furthermore, we compared the cognitive function of wildtype and Rlip+/- mice. Behavioral, basic motor and sensory function tests in Rlip+/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function, and CREB signaling genes in the Rlip+/- mouse liver. Our results suggest that the Rlip deficiency-associated increase in OS and mitochondrial dysfunction could contribute to the development of OS-related AD processes. Therefore, the restoration of Rlip activity and endogenous cytoprotective mechanisms by pharmacological interventions is a novel approach to protect against AD.

neuroscience↗

bioRxiv2021

Self-transfecting GMO-PMO and PMO-GMO chimeras enable gene silencing in vitro and in vivo zebrafish model and NANOG Inhibition Induce the Apoptosis in Breast and Prostate Cancer Cells

Phosphorodiamidate Morpholino Oligonucleotides (PMOs)-based antisense reagents cannot enter inside cells by itself without the help of any delivery technique which is the last hurdle for their clinical applications. To overcome this limitation, a self-transfecting GMO-PMO or PMO-GMO chimeras has been explored as a gene silencing reagent where GMO stands for guanidinium morpholino oligonucleotides which linked either at the OH- or NH-end of PMOs. GMO not only facilitates cellular internalization of such chimeras but also participates in Watson-Crick base pairing during gene silencing in ShhL2 cells when designed against mGli1 and compared with scrambled GMO-PMO where mutations were made only to the GMO part. GMO-PMO-mediated knockdown of no tail gene resulted no tail-dependent phenotypes in zebrafish and worked even after the delivery at 16-, 32- and 64-cell stages which were previously unachievable by regular PMO. Furthermore, GMO-PMO chimeras has shown the inhibition of NANOG, a key regulator of self-renewal and pluripotency of both embryonic and cancer stem cells. Its inhibition influences on the expression of other cancer related proteins and the respective phenotypes in breast cancer cells and increases the therapeutic potential of taxol. To the best of our knowledge, this is the first report on the self-transfecting antisense reagents since the discovery of guanidinium linked DNA (DNG) and most effective among the all cell-penetrating PMOs reported till date expected to solve the longstanding problem of PMO delivery. In principle, this technology could be useful for the inhibition of any target gene without using any delivery vehicle and should have applications in the fields of antisense therapy, diagnostic and nanotechnology area. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/447039v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1374f3forg.highwire.dtl.DTLVardef@33ca57org.highwire.dtl.DTLVardef@292959org.highwire.dtl.DTLVardef@599b5f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗