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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 55 records · Page 3Linked to original sources

bioRxiv2017

A cortical immune network map identifies a subset of human microglia involved in Tau pathology

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five gene modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 541 subjects from two cohort studies of brain aging. Two of these transcriptional programs - modules 113 and 114 - relate to the accumulation of {beta}-amyloid, while module 5 relates to tau pathology. These modules are also detectable in the human brain's epigenome, where we replicate these associations. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that VASP, a representative module 5 gene, encodes a protein that is upregulated in activated microglia in AD.

neuroscience↗

bioRxiv2018

Systems pathology analysis identifies neurodegenerative nature of age-related retinal diseases

Aging is a phenomenon associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. The iERM is characterized by fibrous tissue developing on the surface of the macula, leading to biomechanical and biochemical macular damage. MH is a small breakage in the macula associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry based label-free quantitative proteomics analysis of the vitreous proteomes from patients with iERM (n=26) and MH (n=21) to identify the key proteins as well as the multiple interconnected biochemical pathways contributing to the development of these diseases. We identified a total of 1014 unique proteins, of which many were linked to inflammation and complement cascade, revealing the inflammational processes in retinal diseases. Additionally, we detected a profound difference in proteomes of the iEMR and MH compared to the non-proliferative diabetic retinopathy. A large number of neuronal proteins were present at higher levels in iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins and signalling molecules. This points toward the important role of neurodegeneration component in the pathogenesis of age-related vitreoretinal diseases. Despite of marked similarities, several unique vitreous proteins were identified in both iERM and MH conditions, providing a candidate targets for diagnostic and new therapeutic approaches. Identification of previously reported and novel proteins in human vitreous humor from patient with iERM and MH provide renewed understanding of the pathogenesis of age-related vitreoretinal diseases.

biochemistry↗

bioRxiv2018

Quantitative analysis of synaptic pathology and neuroinflammation: an initial study in a female rhesus monkey model of the “synaptic” phase of Alzheimer’s disease

BackgroundSoluble oligomers of the A{beta} peptide (A{beta}Os) are toxins that target and disrupt synapses. Generation of A{beta}Os has been recently recognized as a probable initiating event in Alzheimers disease (AD), leading to cognitive impairment. There is a translational gap in AD studies, with promising drugs developed based on work in rodent models failing in AD patients in clinical trials. Additionally, although women have a two-fold greater lifetime risk of developing AD compared to men, females have not been a focus of preclinical studies. Thus, we sought to develop a model of A{beta}O toxicity in female rhesus monkeys, to take advantage of the more highly differentiated cortical structure in this species as well as the similarities in the endocrine system between rhesus monkeys and humans.\n\nMethodsRepeated intracerebroventricular (i.c.v) injections of A{beta}Os were performed in adult female rhesus monkeys. Controls were unoperated aged matched monkeys. High-resolution confocal microscopy and morphometric analysis of Alexa 568 (A568) filled neurons were used to evaluate synaptic, neuronal, and glial markers in the dorsolateral prefrontal cortex (dlPFC) and hippocampus after A{beta}O injections. Cerebrospinal fluid (CSF) and brain tissue were also collected and analyzed for biomarkers of AD pathology, including: phosphorylated Tau protein (pTau), total Tau, A{beta}1-42, A{beta}1-40 and TNF- levels.\n\nResultsHere, we report that A{beta}O injection into the lateral ventricle of the brain induces loss of 37% of thin spines in targeted dlPFC neurons, an area highly vulnerable in AD and aging. Further, A{beta}Os associate with the synaptic marker PSD95, inducing loss of more than 60% of local excitatory synapses. A{beta}Os induce a robust neuroinflammatory response in the hippocampus, far from the injection site, with numerous activated ameboid microglia and TNF- release. Finally, A{beta}Os increased CSF levels of A{beta}1-42, pTau Ser396 and pTau Ser199, but not A{beta}1-40 or total Tau.\n\nConclusionsThese initial findings from detailed quantitative analysis of effects of A{beta}O administration on synapses in a female nonhuman primate model are a very promising step toward understanding the mechanism of early AD pathogenesis in the primate brain, and may help develop an effective disease-modifying therapy of high relevance to womens health.

neuroscience↗

bioRxiv2018

Epigenome-wide study uncovers tau pathology-driven changes of chromatin organization in the aging human brain

Accumulation of tau and amyloid-{beta} are two pathologic hallmarks of Alzheimers disease (AD). Here, we conducted an epigenome-wide association study using the H3K9 acetylation (H3K9Ac) mark in 669 aged human prefrontal cortices: in contrast to amyloid-{beta}, tau protein burden had a broad effect on the epigenome, affecting 5,590 out of 26,384 H3K9Ac domains. Tau-related alterations aggregated in large genomic segments reflecting spatial chromatin organization, and the magnitude of these effects correlated with the segments nuclear lamina association. We confirmed the functional relevance of these chromatin changes by demonstrating (1) consistent transcriptional changes in three independent datasets and (2) similar findings in two AD mouse models. Finally, we found that tau overexpression in iPSC-derived neurons disrupted chromatin organization and that these effects could be blocked by a small molecule predicted to reverse the tau effect. Thus, we report large-scale tau-driven chromatin rearrangements in the aging human brain that may be reversible with HSP90 inhibitors.

neuroscience↗

bioRxiv2018

Pathological Oxidation of PTPN12 Underlies ABL1 Phosphorylation in HLRCC

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germ line inactivating alterations in Fumarate Hydratase (FH) cause HLRCC, and result in elevated levels of reactive oxygen species (ROS). Recent work indicates that FH -/-PRCC cells have increased ABL1 activation, which promotes tumor growth, but how ABL1 is activated remained unclear. Oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity; conceivably, ROS-catalyzed inactivation of an ABL-directed PTP might account for ABL1 activation in this malignancy. Previously, our group developed \"q-oxPTPome,\" a method that can globally monitor the oxidation of classical PTPs. We have now refined the q-oxPTPome approach, increasing its sensitivity by >10X. Applying q-oxPTPome to FH-deficient cell models shows that multiple PTPs are either highly oxidized (including PTPN12) or overexpressed. In general, highly oxidized PTPs were those that have relatively high sensitivity to exogenous H2O2. Most PTP oxidation in FH-deficient cells is reversible, although nearly 40% of PTPN13 is oxidized irreversibly to the sulfonic acid state. Using \"substrate-trapping mutants\", we mapped PTPs to their putative substrates, and found that only PTPN12 could target ABL1. Furthermore, knockdown experiments identify PTPN12 as the major ABL1 phosphatase in HLRCC. Overall, our results show that ROS-induced PTPN12 oxidation accounts for ABL1 phosphorylation in HLRCC-associated PRCC, reveal a novel mechanism for inactivating a tumor suppressor gene product, and establish a direct link between pathological PTP oxidation and neoplastic disease.

cancer biology↗

bioRxiv2018

High resolution profile of body wide pathological changes induced by abnormal elastin metabolism in Loxl1 knockout mice

Abnormal ECM caused serious body wide diseases and elastin is one of the important ECM components. But its systemic function still has not yet been thoroughly illustrated due to limitations related to novel research technologies. To uncover the functions of elastin, a new method for body-wide organ transcriptome profiling, combined with single-cell mass cytometry of the blood, was developed. A body-wide organ transcriptomic (BOT) map was created by performing RNA-seq of 17 organs from both Loxl1 knockout (KO) and wide type (WT) mice. The BOT results showed a systematic up-regulation of genes related to immune response and proliferation process in multiple tissues of the KO mice; histological and immune staining also confirmed the hyperplasia and infiltration of local immune cells in the vagina, small intestine, and liver tissues of KO mice. Furthermore, using 32 markers, CYTOF mass cytometry analysis of the immune cell subpopulations from the peripheral blood revealed apparent systemic immune changes in the KO mice; data showed an activated NK cells and T cells with a higher expression of CD44 and CD38, and a suppressed B cells, macrophages and neutrophils with lower expressions of CD62L, CD44 and IL6. More interestingly, these findings also correlated well with the data obtained from cancer patient databases; tumor patients had higher mutation frequency of Loxl1, and the Loxl1-mutant tumor patients had up-regulated immune process, cell proliferation and decreased survival rate. Thus, this research provided a powerful strategy to screen body-wide organ functions of a particular gene; the findings also illustrated the important biological roles of elastin on multiple organ cells and systemic immunity. These strategy and discoveries are both of important value for the understanding of ECM biology and multi-organ cancer pathology.

cancer biology↗

bioRxiv2018

Ras inhibition by trametinib treatment in Drosophila attenuates gut pathology in females and extends lifespan in both sexes

Females of most species live longer than do males. Furthermore, lifespan-extending interventions in laboratory model organisms are often more effective in females (Regan and Partridge 2013). For instance, genetic and pharmacological suppression of activity of the insulin/insulin-like signalling - target of rapamycin (IIS-TOR) network generally extends female lifespan more than that of males in both Drosophila and mice (Clancy et al. 2001; Selman et al. 2009). We previously showed that attenuation of Ras-dependent IIS signalling by treatment with the FDA-approved MEK inhibitor, trametinib extends lifespan in females (Slack et al. 2015). Here, we demonstrate that trametinib treatment has beneficial effects on female-specific, age-related gut pathologies, similar to those obtained through dietary restriction (Regan et al. 2016). Importantly, we identify Ras inhibition as an effective lifespan-extending manipulation in males as well as females, pointing to parallel mechanisms of lifespan extension by trametinib in both sexes.

physiology↗

bioRxiv2018

Quantitative evaluation of ontology design patterns for combining pathology and anatomy ontologies

Data are increasingly annotated with multiple ontologies to capture rich information about the features of the subject under investigation. Analysis may be performed over each ontology separately, but, recently, there has been a move to combine multiple ontologies to provide more powerful analytical possibilities. However, it is often not clear how to combine ontologies or how to assess or evaluate the potential design patterns available. Here we use a large and well-characterized dataset of anatomic pathology descriptions from a major study of aging mice. We show how different design patterns based on the MPATH and MA ontologies provide orthogonal axes of analysis, and perform differently in over-representation and semantic similarity applications. We discuss how such a data-driven approach might be used generally to generate and evaluate ontology design patterns.

bioinformatics↗

bioRxiv2018

Non-coding Class Switch Recombination-related transcription in human normal and pathological immune responses

BackgroundAntibody class switch recombination (CSR) to IgG, IgA or IgE is a hallmark of adaptive immunity, allowing antibody function diversification beyond IgM. CSR involves a deletion of the IgM/IgD constant region genes placing a new acceptor Constant (CH) gene, downstream of the VDJH exon. CSR depends on non-coding (CSRnc) transcription of donor I and acceptor IH exons, located 5 upstream of each CH coding gene. Although our knowledge of the role of CSRnc transcription has advanced greatly, its extension and importance in healthy and diseased humans is scarce.\n\nMethodsWe analyzed CSRnc transcription in 70,603 publicly available RNA-seq samples, including GTEx, TCGA and the Sequence Read Archive (SRA) using recount2, an online resource consisting of normalized RNA-seq gene and exon counts, as well as coverage BigWig files that can be programmatically accessed through R. CSRnc transcription was validated with a qRT-PCR assay for I, I{gamma}3 and I{gamma}1 in humans in response to vaccination.\n\nResultsWe mapped IH transcription for the human IgH locus, including the less understood IGHD gene. CSRnc transcription was restricted to B cells and is widely distributed in normal adult tissues, but predominant in blood, spleen, MALT-containing tissues, visceral adipose tissue and some so-called \"immune privileged\" tissues. However, significant I{gamma}4 expression was found even in non-lymphoid fetal tissues. CSRnc expression in cancer tissues mimicked the expression of their normal counterparts, with notable pattern changes in some common cancer subsets. CSRnc transcription in tumors appears to result from tumor infiltration by B cells, since CSRnc transcription was not detected in corresponding tumor-derived immortal cell lines. Additionally, significantly increased I5 transcription in ileal mucosa in Crohns disease with ulceration was found.\n\nConclusionsCSRnc transcription occurs in multiple anatomical locations beyond classical secondary lymphoid organs, representing a potentially useful marker of effector B cell responses in normal and pathological immune responses. The pattern of IH exon expression may reveal clues of the local immune response (i.e. cytokine milieu) in health and disease. This is a great example of how the public recount2 data can be used to further our understanding of transcription, including regions outside the known transcriptome.

immunology↗

bioRxiv2018

Unified single-cell analysis of testis gene regulation and pathology in 5 mouse strains

By removing the confounding factor of cellular heterogeneity, single cell genomics can revolutionize the study of development and disease, but methods are needed to simplify comparison among individuals. To develop such a framework, we assayed the transcriptome in 62,600 single cells from the testes of wildtype mice, and mice with gonadal defects due to disruption of the genes Mlh3, Hormad1, Cul4a or Cnp. The resulting expression atlas of distinct cell clusters revealed novel markers and new insights into testis gene regulation. By jointly analysing mutant and wildtype cells using a model-based factor analysis method, SDA, we decomposed our data into 46 components that identify novel meiotic gene regulatory programmes, mutant-specific pathological processes, and technical effects. Moreover, we identify, de novo, DNA sequence motifs associated with each component, and show that SDA can be used to impute expression values from single cell data. Analysis of SDA components also led us to identify a rare population of macrophages within the seminiferous tubules of Mlh3-/- and Hormad1-/- testes, an area typically associated with immune privilege. We provide a web application to enable interactive exploration of testis gene expression and components at http://www.stats.ox.ac.uk/~wells/testisAtlas.html

genomics↗

bioRxiv2018

Degradation of the extracellular matrix is part of the pathology of ulcerative colitis

The scientific value of re-analyzing existing datasets is often proportional to the complexity of the data. Proteomics data are inherently complex and can be analyzed at many levels, including proteins, peptides, and post-translational modifications to verify and/or develop new hypotheses. In this paper, we present our re-analysis of a previously published study comparing colon biopsy samples from ulcerative colitis (UC) patients to non-affected controls. In addition to confirming and reinforcing the original finding of upregulation of neutrophil extracellular traps (NETs), we report novel findings, including that Extracellular Matrix (ECM) degradation and neutrophil maturation are involved in the pathology of UC. The pharmaceutically most relevant differential protein expressions were confirmed using immunohistochemistry as an orthogonal method. As part of this study, we also compared proteomics data to previously published mRNA expression data. These comparisons indicated compensatory regulation at transcription levels of the ECM proteins we identified and open possible new venues for drug discovery.

molecular biology↗

bioRxiv2018

Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of FSHD

DUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). While DUX4s transcriptional activity has been extensively characterized, the DUX4-induced proteome remains undescribed. Here, we report concurrent measurement of RNA and protein levels in DUX4-expressing cells via RNA-seq and quantitative mass spectrometry. DUX4 transcriptional targets were robustly translated, confirming the likely clinical relevance of proposed FSHD biomarkers. However, a multitude of mRNAs and proteins exhibited discordant expression changes upon DUX4 expression. Our dataset revealed unexpected proteomic, but not transcriptomic, dysregulation of diverse molecular pathways, including Golgi apparatus fragmentation, as well as extensive post-transcriptional buffering of stress response genes. Key components of RNA degradation machineries, including UPF1, UPF3B, and XRN1, exhibited suppressed protein, but not mRNA, levels, explaining the build-up of aberrant RNAs that characterizes DUX4-expressing cells. Our results provide a resource for the FSHD community and illustrate the importance of post-transcriptional processes to DUX4-induced pathology.

genomics↗

bioRxiv2018

A TauP301L mouse model of dementia; development of pathology, synaptic transmission, microglial response and cognition throughout life

BackgroundLate stage Alzheimers disease and other dementias are associated with neurofibrillary tangles and neurodegeneration. Here we describe a mouse (TauD35) carrying human Tau with the P301L mutation that results in Tau hyperphosphorylation and tangles. Previously we have compared gene expression in TauD35 mice to mice which develop plaques but no tangles. A similar comparison of other pathological features throughout disease progression is made here between amyloid{beta} and Tau mice described in Parts I and II of this study.\n\nMethodsIn vitro CA1 patch clamp and field recordings were used to investigate synaptic transmission and plasticity. Plaque load and microglia were investigated with immunohistochemistry. Cognition, locomotor activity and anxiety-related behaviours were assessed with a forced-alternation T-maze, open field and light/dark box.\n\nResultsTransgene copy number in TauD35 mice fell into two groups (HighTAU and LowTAU), allowing assessment of dose-dependent effects of overexpression and resulting in tangle load increasing 100-fold for a 2-fold change in protein levels. Tangles were first detected at 8 (HighTAU) or 13 months (LowTAU) but the effects on synaptic transmission and plasticity and behaviour were subtle. However severe neurodegeneration occurred in HighTAU mice at around 17 months preceded by considerable proliferation but little additional activation of microglia. Proliferation only started as neurodegeneration began at 13 months. Similarly to HighTau mice at 13 months of age, LowTAU mice at 24 months of age showed a comparable tangle load and microglial proliferation. However, LowTAU mice showed no neurodegeneration at this stage and considerable microglial activation, stressing the dependence of these effects on overexpression and/or age.\n\nConclusionsComparison of the effects of amyloid{beta} and plaques without tangles in a model of preclinical Alzheimers disease to the effects of tangles without amyloid{beta} plaques in the late stage model described here may clarify the progressive stages of Alzheimers disease. While Tau hyperphosphorylation and neurofibrillary tangles are eventually sufficient to cause severe neurodegeneration, initial effects on synaptic transmission and the immune response are subtle. In contrast while even with a heavy plaque load little if any neurodegeneration occurs, considerable effects on synaptic transmission and the immune system result, even before plaques are detectable.

neuroscience↗

bioRxiv2018

SorCS2 controls functional expression of amino acid transporter EAAT3 to protect neurons from oxidative stress and epilepsy-induced pathology

The family of VPS10P domain receptors emerges as central regulator of intracellular protein sorting in neurons with relevance for various brain pathologies. Here, we identified a unique role for the family member SorCS2 in protection of neurons from oxidative stress and from epilepsy-induced cell death. We show that SorCS2 acts as sorting receptor that targets the neuronal amino acid transporter EAAT3 to the plasma membrane to facilitate import of cysteine, required for synthesis of the reactive oxygen species scavenger glutathione. Absence of SorCS2 activity causes aberrant transport of EAAT3 to lysosome for catabolism and impairs cysteine uptake. As a consequence, SorCS2-deficient mice exhibit oxidative brain damage that coincides with enhanced neuronal cell death and increased mortality during epilepsy. Our findings highlight a protective role for SorCS2 in neuronal stress response and provide an explanation for upregulation of the receptor seen in surviving neurons of the human epileptic brain.

neuroscience↗

bioRxiv2018

ALS mice carrying pathological mutant TDP-43, but not mutant FUS, display axonal transport defects in vivo

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in the basic neuronal process of axonal transport have been identified in several ALS models. However, in vivo evidence of early/pre-symptomatic deficiencies in neuronal cargo trafficking remains limited, thus the pathogenic importance of axonal transport to the ALS disease spectrum remains to be fully resolved. We therefore analysed the in vivo dynamics of retrogradely transported, neurotrophin-containing signalling endosomes in motor neuron axons of two new mouse models of ALS that have mutations in different RNA processing genes (Tardbp and Fus). TDP-43M337V mice, which show neuromuscular pathology but no overt motor neuron loss, displayed in vivo perturbations in axonal transport that manifested between 1.5 and 3 months and preceded motor symptom onset. In contrast, signalling endosome transport remained largely unaffected in mutant Fus{Delta}14/+ mice, despite 20% motor neuron loss. These findings indicate that deficiencies in retrograde neurotrophin signalling and axonal transport are not common to all ALS-linked genes, and that there are inherent and mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes.

neuroscience↗

bioRxiv2016

Stratifying risk of prostate cancer recurrence following external beam radiation therapy: Comparing prostate MRI with prostate biopsy pathology.

Abbreviations Abbreviations INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION Conflict of Interests Statement References (DIPL), Dominant intraprostatic lesion\n\n(DN), Dominant nodule\n\n(EBRT), External Beam Radiation Therapy\n\n(ECE), Extracapsular Extension\n\n(NVB), Neurovascular Bundle Invasion\n\n(SVI), Seminal Vesicle Invasion\n\n(MIBC), Maximum involvement of any biopsy core\n\n(PCV), Percentage of cancer volume\n\n(PPBC), Percentage of positive biopsy cores\n\n(NCCN), National Comprehensive Cancer Network\n\nINTRODUCTION Abbreviations INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION ...

Pathology↗

bioRxiv2016

A genetic test for differential causative pathology in disease subgroups

Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in the two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximising power in comparison to a standard variant by variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post-hoc identification of the contributing genetic variants.\n\nWe demonstrate the method on a range of simulated and test datasets where expected results are already known. We investigate subgroups of type 1 diabetes (T1D) cases defined by autoantibody positivity, establishing evidence for differential genetic architecture with thyroid peroxidase antibody positivity, driven generally by variants in known T1D associated regions.

Genomics↗

bioRxiv2016

Mice deficient of Myc super-enhancer region reveal a differential control mechanism between normal and pathological growth

The gene desert upstream of the Myc oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer, including cancers of breast, prostate, and colon. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50 to 80% decrease in MYC expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. Consistently, deletion of the 8q24 super-enhancer region perturbs Myc targets only in cultured cells, but not in vivo. These results reveal that only cells whose Myc activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.

cancer biology↗