Biology subjects

Coleman, E.

Publications and source records attributed to Coleman, E..

5 recordsLinked to original sources

bioRxiv2026

Ontological Analysis of Brain Proteostasis Highlights the Sex-Dependent Trajectory of ApoE Isoform-Specific Regulation

Apolipoprotein E (ApoE) is the strongest genetic predictor of Alzheimers disease (AD) risk, with ApoE4 increasing and ApoE2 decreasing risk relative to ApoE3. Using a global LC-MS proteomic approach, we integrated protein abundance and kinetics in Human-APOE knock-in mice for young (3-month) and aged (18-month) cohorts to quantify the changes in steady-state proteostasis. By mapping 6,052 identified proteins and 3,986 associated turnover rates into ontological groups, we observed that vesicle trafficking and mitochondrial dysregulation occur as early as 3 months in ApoE4 mice accompanied by hyperactive metabolism that eventually reduces with age. In contrast, young and old ApoE2 mice retain similar signatures to ApoE3 mice in metabolic, mitochondrial, cellular regulation, and membrane trafficking ontologies. We found that females had more isoform-induced ontological changes relative to ApoE3, providing insight into sex-dependent vulnerabilities. Our global proteomic approach for ApoE proteostasis crucially unifies independent literature observations while providing turnover kinetics to uncover the underlying mechanism behind abundance changes. Data are available via ProteomeXchange with identifier PXD079261. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/735293v1_ufig2.gif" ALT="Figure 1000"> View larger version (45K): org.highwire.dtl.DTLVardef@28ebfforg.highwire.dtl.DTLVardef@9dc6f2org.highwire.dtl.DTLVardef@704577org.highwire.dtl.DTLVardef@e0b0e2_HPS_FORMAT_FIGEXP M_FIG C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/735293v1_ufig1.gif" ALT="Figure 1001"> View larger version (48K): org.highwire.dtl.DTLVardef@17d0474org.highwire.dtl.DTLVardef@af771borg.highwire.dtl.DTLVardef@1b49f67org.highwire.dtl.DTLVardef@14d3aa2_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Stopping and Changing Expected and Unexpected Movements

The capacity to cancel or adapt planned actions in response to changing environmental demands is essential for navigating our complex world. While past research has shown that an individuals expectations of upcoming movement demands influence the speed of action initiation, the effect this has on subsequent cancellation or adaption of that movement remains unknown. 25 healthy adults completed stop signal tasks and stop change tasks in which biasing cues (e.g., "70% left") accurately indicated the probability that a left, or right button press would be required. As expected, responses that were congruent with the cue were faster than incongruent responses; however, biasing cues had no effect on behavioural or physiological (electromyographical) indices of stopping speed. Stopping latencies were found to be faster in the stop change task than the stop signal task, corroborating other recent work. However, a second experiment (25 healthy adults) which used the same stimuli for both tasks (varying only the instructions), revealed no difference - highlighting the sensitivity of the stop process to stimulus effects, and a common confound in the literature. We also observed that physiological indices of action reprogramming (following a stop) were faster in congruent than incongruent trials. Collectively, these results suggests that preparatory changes that accompany expected movements influence the enaction of movement both prior to, and after stopping, but the stop mechanism itself, remains independent of these preparations. These results inform how action cancellation and adaption are applied in real world environments, where expectations continually interface with our motor plans. HighlightsO_LI* Anticipating a movement increases the speed of its enaction but not subsequent cancellation C_LIO_LI* Expected movements can be reprogrammed more quickly than unexpected movements C_LIO_LI* The latency of action cancellation is highly sensitive to stimulus effects C_LI

neuroscience↗

bioRxiv2025

An Amygdalar Oscillatory Switch Governs Valence Assignment

Reward pursuit and punishment avoidance are among the most fundamental behaviors necessary for survival. The binary valuation of an experience as either positive or negative - "valence assignment" - is imperative for successful navigation of a regularly updating environment. Mounting evidence highlights the critical role of valence responsive basolateral amygdala (BLA) ensembles in coding valence information. However, how BLA ensembles are recruited to drive real-time valence assignment remains elusive. Here, we show locus coeruleus (LC)-derived norepinephrine coordinates this neural computational process via modulatory control over network-organizing BLA parvalbumin-expressing (PV) interneuron activity. Specifically, optogenetic activation of LC to BLA noradrenergic terminals (LC-BLANE) drives real-time negative valence assignment and suppression of BLA fast gamma oscillatory activity via BLA interneuronal 1a adrenergic receptor signaling. Conversely, positive valence assignment also requires BLA PV interneuron activity but is associated with an enhancement of local fast gamma power. Together, these converging data highlight a PV-driven amygdalar oscillatory switch that governs valence assignment.

neuroscience↗

bioRxiv2024

Pharmacological inhibition of Fms-like kinase 3 (FLT3) promotes neuronal maturation and suppresses seizure in a mouse model

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase predominantly expressed in blood and brain cells. While the FLT3 signaling pathway has been extensively studied in blood cell development and leukemia, its role in the brain remains largely unexplored. Through our groups previous high-throughput drug screening work unexpectedly found that several small molecule FLT3 inhibitors (FLT3i), including KW-2449 and Sunitinib, enhance expression of the gene encoding chloride transporter KCC2 in neurons. KCC2 is crucial for brain development and function, and its dysregulation is linked to many brain diseases. These findings suggest previously unrecognized roles of FLT3 signaling in brain health and disease that have yet to be systematically studied. In this study, we utilized a functional genomics approach to investigate the transcriptomic changes induced by pharmacological inhibition of the FLT3 pathway in brain cells, including cultured primary mouse neurons, a human stem cell-derived neuronal model of Rett syndrome (RTT), and human stem cell-derived microglia cultures. Our results show that treating human or mouse neurons with FLT3i drugs significantly upregulates genes crucial for brain development while downregulating genes linked to neuroinflammation. In contrast, FLT3i treatment of human microglia, which do not express FLT3, has no effect on their gene expression, highlighting the cell type-specific roles of FLT3 signaling in the brain. To further understand how FLT3 signaling regulates the expression of neuronal maturation genes such as KCC2, we conducted a curated CRISPR screen that identified a number of transcription factors involved in FLT3i-mediated KCC2 activation in neurons. The mRNA and protein levels of several neurodevelopmental disorder (NDD) risk genes are significantly upregulated in FLT3i-treated neurons, indicating potential therapeutic applications of FLT3i in rescuing underexpression and/or haploinsufficiency of disease-associated genes. In our in vivo studies, we evaluated the efficacy of the FLT3i drug KW-2449 in mice, demonstrating that it can effectively cross the blood-brain barrier, induce KCC2 protein expression for up to 24 hours after a single injection, and reduces seizure activity in a chemoconvulsant-induced mouse model of temporal lobe epilepsy. Collectively, our findings uncover previously unrecognized roles of neuron-specific FLT3 signaling in promoting neuronal maturation and reducing neuroinflammation. These results suggest that FLT3 kinase signaling regulates a transcriptional program vital for brain development and function, position it as a promising therapeutic target for NDD treatment.

neuroscience↗

bioRxiv2023

Tofacitinib effects profound seizure suppression through mimicking EZH2 antagonism of a pro-inflammatory gene network in epilepsy.

All current drug treatments for epilepsy, a neurological disorder affecting over 50 million people(1, 2) merely treat symptoms, and a third of patients do not respond to medication. There are no disease modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits(3, 4). Applying network approaches to rodent models and human temporal lobectomy samples at both whole tissue and single-nuclei resolutions, we observe the well-characterized pattern of rapid induction and subsequent quenching exhibited of the JAK/STAT pathway within days of epileptogenic insult. This is followed by a resurgent activation weeks to months later with the onset of spontaneous seizures. Targeting the first wave of activation after epileptic insult does not prevent disease. However, brief inhibition of the second wave with CP690550 (Tofacitinib) (5, 6) enduringly suppresses seizures, rescues deficits in spatial memory, and alleviates epilepsy-associated histopathological alterations. Seizure suppression lasts for at least 2 months after the final dose. Using discovery-based transcriptomic analysis across models of epilepsy and validation of putative mechanisms with human data, we demonstrate a powerful approach to identifying disease modifying targets; this may be useful for other neurological disorders. With this approach, we find that reignition of inflammatory JAK/STAT3 signaling in chronic epilepsy opens a window for disease modification with the FDA-approved, orally available drug CP690550.

neuroscience↗