Biology subjects

Bailey, H. M.

Publications and source records attributed to Bailey, H. M..

3 recordsLinked to original sources

bioRxiv2025

Integrative analysis reveals generalizable human neurodegenerative disease-associated glial states

Glial cells are known to respond transcriptionally in multiple neurodegenerative diseases (NDDs). In particular, microglial states have been characterized in Alzheimers disease and mouse models of amyloidosis as disease-associated microglia. Although single-cell transcriptomic technologies have increased the dimensionality of information available across cell states, few studies have systematically tested for changes in glial transcription across brain regions and disease states. Here, we report a statistical framework for glial annotation, disease association, and transcriptional profiling, which facilitate identification of generalizable glial states that are present across a spectrum of NDDs (Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis, and frontotemporal dementia) by re-analyzing data available in four multi-region atlases. We identify seven astrocyte substates, 14 microglia/myeloid substates, and five oligodendrocyte substates where transcriptional variability is attributable to region, disease, or study-specific effects. Regional heterogeneity of astrocytes masked disease associations, even within cortical subregions. We found only limited oligodendrocyte transcriptional heterogeneity, resulting in few substates for further interrogation. Notably, microglia showed the strongest evidence for disease association. We show, for the first time, that this association exists across different NDDs. Using latent factor analysis, we created a consensus human neurodegenerative disease-associated microglia (hnDAM) signature, which we experimentally validated in 11 independent sample series. We demonstrate that the hnDAM signature is a statistically testable biomarker for conserved microglial activation in NDDs by: i) comparing to murine DAM-like signatures, ii) performing transcription factor analysis, and iii) modeling transcriptional reprogramming perturbations in iPSC-derived microglia. Importantly, we find for the first time a way to make direct comparisons between DAM-like activation profiles in separate studies and propose a novel modeling paradigm via PIKfyve inhibition. Taken together, this work broadens our understanding of glial activation across neuropathologies and reveals hnDAM as a putative therapeutic target that can be utilized in any transcriptomic study of patients suffering from NDDs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/678630v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1863095org.highwire.dtl.DTLVardef@dfa6c8org.highwire.dtl.DTLVardef@13e95f1org.highwire.dtl.DTLVardef@1e6165e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Localization of Drosophila formin, Cappuccino, influences posterior oocyte organization

AbstractCappuccino (Capu) and Spire build actin networks in numerous systems, including the mouse oocyte, melanocytes, and the Drosophila oocyte. As observed in mammalian systems, the localization of the Capu homologues (FMN1/2), influences the function of the actin network. Therefore, we established and interrogated the impact of altering Capus localization in the Drosophila oocyte to better understand its role and that of the actin mesh it builds. This mesh restricts bulk cytoplasmic flows, streaming, but otherwise remains undescribed functionally. Using a gene specific driver, capu-Gal4, to better study Capu transgenes, we found that fertility was markedly decreased when restricting Capu to membranes in the oocyte, although its canonical role in actin mesh assembly was apparently unaltered. Instead, we observed a defect in posterior anchoring of the mRNA oskar during mid-oogenesis. However, the defect did not fall into the traditional posterior group phenotype. The data suggest that Capu, independently of Spire, tethers the posterior determinants to the cortex but does not anchor them to each other, supporting that Capu localization influences the posterior oocyte organization.

developmental biology↗

bioRxiv2019

Spire stimulates nucleation by Cappuccino and binds both ends of actin filaments

An actin mesh fills both mouse and fly oocytes. The meshes are built by a conserved mechanism and used to establish polarity. Two actin nucleators, Spire and Cappuccino, collaborate to build actin filaments that connect vesicles and the cortex. Direct interaction between Spire and Cappuccino is required for in vitro synergistic actin assembly; however, we understand little about why the interaction is necessary. To mimic the geometry of Spire and Cappuccino in vivo, we immobilized Spire on beads. We found that increased nucleation is a major part of synergy and that Spire alone binds both barbed- and pointed-ends of actin filaments. We identified Spires barbed-end binding domain. Partial rescue of fertility by a loss-of-function mutant indicates that barbed-end binding is not necessary for Spires in vivo function, but that it may play a role under normal circumstances. We propose that Spire stimulates nucleation by Cappuccino in a manner similar to the collaboration between APC and mDia1.\n\nSummaryActin nucleators Cappuccino and Spire collaborate to build an actin mesh in oocytes. Data demonstrate that the collaboration leads to synergistic actin nucleation, as opposed to elongation. Further, Spire binds both ends of polar, actin filaments, resolving a long-outstanding question.

biochemistry↗