Biology subjects

Newton, D. F.

Publications and source records attributed to Newton, D. F..

3 recordsLinked to original sources

bioRxiv2024

TDP43 proteinopathy exhibits disease, tissue, and context-specific cryptic splicing signatures

Mislocalization of the nuclear TAR DNA-binding protein 43 (TDP43) is a hallmark of ALS and FTD which leads to de-repression and inclusion of cryptic exons (CEs), promising biomarkers of TDP43 pathology in a spectrum of neurodegenerative diseases. However, most CEs to date have been identified from in vitro models or a single cortical FTD dataset, and little is known about cryptic splicing in the spinal cord, or within different neuronal subtypes. We meta-analyzed published bulk RNAseq datasets representing 1,778 RNAseq profiles of ALS and FTD post-mortem tissue, and in vitro models with experimentally depleted TDP43. We identified 142 cryptic splices, including 68 novel events. We found divergent cryptic splicing primarily between the spinal cord and cortex, validated in an independent ALS cohort by qPCR and supported by in situ hybridization (ISH). We also identified a set of cryptic splices observed in tissue but not in vitro, and, being present in either SOD1-ALS or MAPT-FTD subjects, likely TDP43 independent. Finally, leveraging multiple public single-nucleus RNAseq datasets of ALS and FTD motor and frontal cortex, we confirmed the elevation of cortical-enriched splices in disease and localized them to layer-specific neuronal populations. We provide a web interface to browse the meta-analysis results at https://go.roche.com/CrypticSplicingLandscape. This catalog of cryptic splices will inform efforts to develop biomarkers for tissue-specific and cell type-specific TDP43 pathology.

neuroscience↗

bioRxiv2020

Reduced anterior cingulate cortex volume induced by chronic stress correlates with increased behavioral emotionality and decreased synaptic puncta density

Clinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). Here, we aimed to investigate the volumetric changes associated with chronic restraint stress (CRS) and link these changes to the CRS-induced behavioral and synaptic deficits. We first confirmed that CRS increases behavioral emotionality, defined as collective scoring of anxiety- and anhedonia-like behaviors. We then demonstrated that CRS induced a reduction of total brain volume which negatively correlated with behavioral emotionality. Region-specific analysis identified that only the ACC showed significant decrease in volume following CRS (p<0.05). Reduced ACC correlated with increased behavioral emotionality (r=-0.56; p=0.0003). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Finally, using structural covariance network analysis to assess shared volumetric variances between the corticolimbic brain regions and associated structures, we found a progressive decreased ACC degree and increased AMY degree following CRS. At the cellular level, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r=0.35, p<0.05), which also correlated with increased behavioral emotionality (r=-0.44, p<0.01), suggesting that altered synaptic strength is an underlying substrate of CRS volumetric and behavioral effects. Our results demonstrate that CRS effects on ACC volume and synaptic density are linked to behavioral emotionality and highlight key ACC structural and morphological alterations relevant to stress-related illnesses including mood and anxiety disorders. HighlightsO_LIChronic restraint stress (CRS) decreases anterior cingulate cortex (ACC) volume C_LIO_LIACC and amygdala (AMY) volumes negatively correlate with behavioral emotionality C_LIO_LICRS decreased the strength and degree of the ACC structural covariance network C_LIO_LICRS increased the strength and degree of the AMY structural covariance network C_LIO_LIPSD95 puncta density correlates with behavioral emotionality and ACC volume. C_LI

neuroscience↗

bioRxiv2020

Chronic stress induces coordinated cortical microcircuit cell type transcriptomic changes consistent with altered information processing

Major depressive disorder (MDD) is associated with altered GABAergic and glutamatergic signalling, suggesting altered excitation-inhibition balance (EIB) in cortical mood- and cognition-regulating brain regions. Information processing in cortical microcircuits involves regulation of pyramidal (PYR) cells by Somatostatin-(SST), Parvalbumin-(PV), and Vasoactive intestinal peptide-(VIP) expressing interneurons. Human and rodent studies suggest that impaired PYR-cell dendritic morphology and decreased SST-cell function may mediate altered EIB in MDD. However, knowledge of co-ordinated changes across microcircuit cell types is virtually absent. We thus investigated the co-ordinated transcriptomic effects of UCMS on microcircuit cell types in the medial prefrontal cortex. C57Bl/6 mice, exposed to unpredictable chronic mild stress (UCMS) or control housing for five weeks were assessed for anxiety- and depressive-like behaviours. Microcircuit cell types were laser-microdissected and processed for RNA-sequencing. UCMS-exposed mice displayed predicted elevated behavioural emotionality. Each microcircuit cell type showed a unique transcriptional signature after UCMS. Pre-synaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell types, whereas nearly all cell types showed down-regulated post-synaptic gene signatures. At the microcircuit level, we observed a shift from distributed transcriptomic co-ordination across cell types in controls towards UCMS-induced increased co-ordination between PYR-, SST- and PV-cells, and a hub-like role for PYR-cells. Lastly, we identified a microcircuit-wide co-expression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviours. Together, these findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cortical EIB mediated by increased co-ordinated regulation of PYR-cells by SST- and PV-cells.

neuroscience↗