Biology subjects

Labadorf, A. T.

Publications and source records attributed to Labadorf, A. T..

7 recordsLinked to original sources

bioRxiv2026

Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs

Prion propagation, in which the cellular prion protein (PrPC) is conformationally converted into an infectious structure (PrPSc), is now well understood. However, the molecular mechanism responsible for the neurotoxicity of prions remains unclear. Synaptic loss is one of the earliest events in both in vivo and in vitro models of prion disease. We previously developed a neuronal cell culture model to analyze the mechanisms of prion-induced synaptic degeneration in a physiologically relevant setting. Using this system, we showed that exposure of hippocampal neurons to PrPSc engages a NMDAR/p38 mitogen-activated protein kinase (MAPK) signaling pathway that results in rapid, PrPC-dependent loss of synaptic transmission and retraction of dendritic spines. To comprehensively identify the components of this synaptotoxic signaling pathway, we measured changes in the phosphoproteome and transcriptome of hippocampal neurons exposed to PrPSc while they were undergoing the process of dendritic spine retraction. We then used these data as input into the L1000 and P100 databases of transcriptomic and proteomic drug signatures, leading to the discovery of 17 compounds that were able to prevent PrPSc-induced spine retraction. These compounds converged on three protein kinase targets: Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), and glycogen synthase kinase 3{beta} (GSK3{beta}). Using immunocytochemical staining, we confirmed that PrPSc treatment of hippocampal neurons induced phosphorylation of the three kinases and caused their rapid translocation to dendritic spines. Along with N-methyl-D-aspartate receptors (NMDARs) on the neuronal surface, which trigger an initial influx of Ca2+ in response to PrPSc, these kinases constitute key nodes in a signaling network that mediates prion synaptotoxicity. Taken together, our results provide new insights into the mechanisms of prion neurotoxicity, and they identify novel molecular targets and inhibitory compounds that can be utilized for therapy of prion diseases. AUTHOR SUMMARYThe mechanism by which prions propagate is now well established, but how they cause neurodegenerative changes is still uncertain. The earliest effects of prion infection occur at the level of the synapse, and we previously established an experimental system using cultured hippocampal neurons to assay prion synaptotoxicity. To search comprehensively for components of the synaptotoxic signaling pathway, we employed a novel, small-molecule discovery pipeline based on the transcriptomic and phosphoproteomic profiles of prion-treated neurons. This approach converged on inhibitors of three different protein kinases (Ca2+/calmodulin-dependent protein kinase II, protein kinase C, and glycogen synthase kinase 3{beta}), which, along with N-methyl-D-aspartate receptors, constitute key nodes in a prion synaptotoxic signaling network that can be targeted for therapeutic benefit.

neuroscience↗

bioRxiv2024

Transposable element small and long RNAs in aging brains and implications in Huntington's and Parkinson's disease

Transposable Elements (TEs) are implicated in aging and neurodegenerative disorders, but the impact of brain TE RNA dynamics on these phenomena is not fully understood. Therefore, we quantified TE RNA changes in aging post-mortem human and mouse brains and in the neurodegenerative disorders Huntingtons Disease (HD) and Parkinsons Disease (PD). We tracked TE small RNAs (smRNAs) expression landscape to assess the relationship to the active processing from TE long RNAs (lnRNAs). Human brain transcriptomes from the BrainSpan Atlas displayed a significant shift of TE smRNA patterns at age 20 years, whereas aging mouse brains lacked any such marked change, despite clear shift in aging-associated mRNA levels. Human frontal cortex displayed pronounced sense TE smRNAs during aging with a negative relationship between the TE smRNAs and lnRNAs indicative of age associated regulatory effects. Our analysis revealed TE smRNAs dysregulation in HD, while PD showed a stronger impact on TE lnRNAs, potentially correlating with the early average age of death for HD relative to PD. Furthermore, TE-silencing factor TRIM28 was down-regulated only in aging human brains, possibly explaining the lack of substantial TE RNA changes in aging mouse brains. Our study suggests brain TE RNAs may serve as novel biomarkers of human brain aging and neurodegenerative disorders.

genomics↗

bioRxiv2024

Reading Outside the Lines: A Systematic Approach for Detecting Bias in Scientific Communication

Consciousness of the social impact of science and the potential biases of its authors is critical to understanding, interpreting, and using scientific findings responsibly. This is especially true for sciences concerned with human health and behavior, where societal and unconscious biases may reinforce existing inequities and discriminatory practices. Considering backgrounds and biases, we may notice bias influencing scientists methodological choices and conclusions, even when a work is otherwise scientifically sound. To this end, we created the pedagogical tool Finding inEquity in LIterature and eXperimentation (FELIX). FELIX is a tool that systematizes the detection of bias and subjectivity in scientific communications by using a three-phase progression of (i) Annotation, (ii) Analysis and (iii) Synthesis, where students form a unified argument about the text with a focus on its relationship to social or ethical context. Results from a mixed methods approach indicated the efficacy of our approach in supporting student learning related to reading comprehension, critical thinking skills, and in understanding the social and ethical implications of the research they were reading. We put forward FELIX as a universal method for training students in the reading of scientific communications and as a tool for addressing systemic inequities in science and science education.

scientific communication and education↗

bioRxiv2023

Heterogeneity of novel APOER2 isoforms specific to Alzheimer disease impact cellular and synaptic states

Apolipoprotein receptor 2 (APOER2) is an alternatively spliced transmembrane receptor that binds the neuroprotective ligand Reelin and Alzheimers disease (AD) related risk factor, APOE. Splicing of single exons in mouse Apoer2 regulates neuronal function and synaptic plasticity. However, the splicing landscape and function of human APOER2 isoforms in physiological and AD conditions remains unclear. Here, we identified over 200 unique human APOER2 isoforms in the parietal cortex and hippocampus with 151 isoforms common between the two brain regions. In addition, we identified region- and AD-specific APOER2 isoforms suggesting APOER2 splicing is spatially regulated and altered in AD. We tested whether the AD-specific APOER2 transcripts have distinct functional properties, and demonstrated AD-specific APOER2 variants have altered cell surface expression, APOE-mediated receptor processing and synaptic changes which could contribute to neuronal dysfunction associated with AD pathogenesis.

neuroscience↗

bioRxiv2022

Widespread perturbation of ETS factor binding sites in cancer

Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.

cancer biology↗

bioRxiv2022

Inflammation and neuronal gene expression changes differ in early vs late chronic traumatic encephalopathy brain

Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown. To address these questions, we conducted an analysis of the largest mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on extent of tau pathology and years of play to model early vs late changes in response to exposure, and the relative effects associated with these factors were compared between these groups. Substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, highly increased neuroinflammatory and neuroimmune processes. In contrast, low exposure groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups. Together, these results suggest the early disease process may differ substantially from that observed in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways.

genomics↗

bioRxiv2022

Holobiont transcriptomes for the critically endangered staghorn coral (Acropora cervicornis) from two environmentally distinct sites on Turneffe Atoll, Belize

Historically, staghorn coral (Acropora cervicornis) was a preeminent reef-builder in the Caribbean and Tropical Western Atlantic, where it constructed extensive thickets at 5-20 m depth that supported diverse ecosystems and provided coastal populations with food, storm protection, and income from tourism. In recent decades, A. cervicornis declined precipitously, up to 97% in some localities. To reverse its decline, widespread efforts are underway to characterize the phenotypic and genetic diversity of persisting populations with the goal of restoring them to historical levels by out-planting nursery grown specimens. To support this target, we developed transcriptomes for two A. cervicornis populations located in Turneffe Atoll Marine Reserve, Belize. These populations experience significantly different temperatures, light levels and water currents, and they harbor individuals that differ in key phenotypes. Because differentiating the gene activity of diverse taxa--i.e., coral host, algal photosymbiont, plus associated eukaryotes, bacteria, archaea, and viruses-- is critical to understanding the function of the coral holobiont, we developed a pipeline for parsing transcripts by taxon. Separate transcriptomes for each population contain complete representatives for >96% of 978 conserved metazoan single copy orthologs. The taxonomic breakdown of transcripts differed between sites, with more bacterial transcripts recovered from Calabash Caye and more symbiont transcripts from Blackbird Caye. The assembled transcriptomes will facilitate gene expression studies and in silico cloning from this endangered coral.

genomics↗