Species-level identification of enterotype-specific microbial markers for colorectal cancer and adenoma.

Enterotypes have been shown to be an important factor for population stratification based on gut microbiota composition, leading to a better understanding of human health and disease states. Classifications based on compositional patterns will have implications for personalized microbiota-based solutions. There have been limited enterotype based studies on colorectal adenoma and cancer. Here, an enterotype-based meta-analysis of fecal shotgun metagenomic studies was performed, including 1579 samples of healthy controls (CTR), colorectal adenoma (ADN) and colorectal cancer (CRC) in total. Gut microbiota of healthy people were clustered into three enterotypes (Ruminococcus-, Bacteroides- and Prevotella-dominated enterotypes). Reference-based enterotype assignments were performed for CRC and ADN samples, using the supervised machine learning algorithm, K-nearest neighbors. Differential abundance analyses and random forest classification were conducted on each enterotype between healthy controls and CRC-ADN groups, revealing novel enterotype-specific microbial markers for non-invasive CRC screening strategies. Furthermore, we identified microbial species unique to each enterotype that play a role in the production of secondary bile acids and short-chain fatty acids, unveiling the correlation between cancer-associated gut microbes and dietary patterns. The enterotype-based approach in this study is promising in elucidating the mechanisms of differential gut microbiome profiles, thereby improving the efficacy of personalized microbiota-based solutions.

A network-based drug prioritization and combination analysis for the MEK5/ERK5 pathway in breast cancer.

BACKGROUND: Prioritizing candidate drugs based on genome-wide expression data is an emerging approach in systems pharmacology due to its holistic perspective for preclinical drug evaluation. In the current study, a network-based approach was proposed and applied to prioritize plant polyphenols and identify potential drug combinations in breast cancer. We focused on MEK5/ERK5 signalling pathway genes, a recently identified potential drug target in cancer with roles spanning major carcinogenesis processes. RESULTS: By constructing and identifying perturbed protein-protein interaction networks for luminal A breast cancer, plant polyphenols and drugs from transcriptome data, we first demonstrated their systemic effects on the MEK5/ERK5 signalling pathway. Subsequently, we applied a pathway-specific network pharmacology pipeline to prioritize plant polyphenols and potential drug combinations for use in breast cancer. Our analysis prioritized genistein among plant polyphenols. Drug combination simulations predicted several FDA-approved drugs in breast cancer with well-established pharmacology as candidates for target network synergistic combination with genistein. This study also highlights the concept of target network enhancer drugs, with drugs previously not well characterised in breast cancer being prioritized for use in the MEK5/ERK5 pathway in breast cancer. CONCLUSION: This study proposes a computational framework for drug prioritization and combination with the MEK5/ERK5 signaling pathway in breast cancer. The method is flexible and provides the scientific community with a robust method that can be applied to other complex diseases.

Effect of RNA-Seq data normalization on protein interactome mapping for Alzheimer's disease.

High throughput RNA sequencing brings new perspective to the elucidation of molecular mechanisms of diseases. Normalization is the first and most important step for RNA-Seq data, and it can differ based on the purpose of the analysis. Within-sample normalization methods (eg. TPM) are preferred when genes in a sample are compared with each other, and between-sample normalization methods (eg. deseq2, TMM, Voom) are used when the samples in a dataset are compared. Normalization approaches rescale the data, and, therefore, they affect the results of the analysis. Here, we selected two most commonly used Alzheimer's disease RNA-Seq datasets from ROSMAP and Mayo Clinic cohorts and mapped the differentially expressed genes on human protein interactome to discover disease-specific subnetworks. To this end, the raw count data were first processed with four different, commonly used RNA-Seq normalization methods (deseq2, TMM, Voom and TPM). Then, covariate adjustment was applied to the normalized data for gender, age of death and post-mortem interval. Each normalized dataset was separately mapped on the human protein-protein interaction network either in covariate-adjusted or non-adjusted form. Capturing known Alzheimer's disease genes and genes associated with the disease-related functional terms in the discovered subnetworks were the criteria to compare different normalization methods. Based on our results, applying covariate adjustment has a positive effect on normalization by removing the confounder effects. Covariate-adjusted TMM and covariate-adjusted deseq2 methods performed better in both transcriptome datasets.

Transcriptome-based biomarker prediction for Parkinson's disease using genome-scale metabolic modeling.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Identification of PD biomarkers is crucial for early diagnosis and to develop target-based therapeutic agents. Integrative analysis of genome-scale metabolic models (GEMs) and omics data provides a computational approach for the prediction of metabolite biomarkers. Here, we applied the TIMBR (Transcriptionally Inferred Metabolic Biomarker Response) algorithm and two modified versions of TIMBR to investigate potential metabolite biomarkers for PD. To this end, we mapped thirteen post-mortem PD transcriptome datasets from the substantia nigra region onto Human-GEM. We considered a metabolite as a candidate biomarker if its production was predicted to be more efficient by a TIMBR-family algorithm in control or PD case for the majority of the datasets. Different metrics based on well-known PD-related metabolite alterations, PD-associated pathways, and a list of 25 high-confidence PD metabolite biomarkers compiled from the literature were used to compare the prediction performance of the three algorithms tested. The modified algorithm with the highest prediction power based on the metrics was called TAMBOOR, TrAnscriptome-based Metabolite Biomarkers by On-Off Reactions, which was introduced for the first time in this study. TAMBOOR performed better in terms of capturing well-known pathway alterations and metabolite secretion changes in PD. Therefore, our tool has a strong potential to be used for the prediction of novel diagnostic biomarkers for human diseases.

Personalized Protein-Protein Interaction Networks Towards Unraveling the Molecular Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is a highly heterogenous neurodegenerative disease, and several omic-based datasets were generated in the last decade from the patients with the disease. However, the vast majority of studies evaluate these datasets in bulk by considering all the patients as a single group, which obscures the molecular differences resulting from the heterogeneous nature of the disease. In this study, we adopted a personalized approach and analyzed the transcriptome data from 403 patients individually by mapping the data on a human protein-protein interaction network. Patient-specific subnetworks were discovered and analyzed in terms of the genes in the subnetworks, enriched functional terms, and known AD genes. We identified several affected pathways that could not be captured by the bulk comparison. We also showed that our personalized findings point to patterns of alterations consistent with the recently suggested AD subtypes.

A new metabolic model of Drosophila melanogaster and the integrative analysis of Parkinson's disease.

High conservation of the disease-associated genes between flies and humans facilitates the common use of Drosophila melanogaster to study metabolic disorders under controlled laboratory conditions. However, metabolic modeling studies are highly limited for this organism. We here report a comprehensively curated genome-scale metabolic network model of Drosophila using an orthology-based approach. The gene coverage and metabolic information of the draft model derived from a reference human model were expanded via Drosophila-specific KEGG and MetaCyc databases, with several curation steps to avoid metabolic redundancy and stoichiometric inconsistency. Furthermore, we performed literature-based curations to improve gene-reaction associations, subcellular metabolite locations, and various metabolic pathways. The performance of the resulting Drosophila model (8,230 reactions, 6,990 metabolites, and 2,388 genes), iDrosophila1 (https://github.com/SysBioGTU/iDrosophila), was assessed using flux balance analysis in comparison with the other currently available fly models leading to superior or comparable results. We also evaluated the transcriptome-based prediction capacity of iDrosophila1, where differential metabolic pathways during Parkinson's disease could be successfully elucidated. Overall, iDrosophila1 is promising to investigate system-level metabolic alterations in response to genetic and environmental perturbations.

Brain-wide transcriptome-based metabolic alterations in Parkinson's disease: human inter-region and human-experimental model correlations.

Alterations in brain metabolism are closely associated with the molecular hallmarks of Parkinson's disease (PD). A clear understanding of the main metabolic perturbations in PD is therefore important. Here, we retrospectively analysed the expression of metabolic genes from 34 PD-control post-mortem human brain transcriptome data comparisons from literature, spanning multiple brain regions. We found high metabolic correlations between the Substantia nigra (SN)- and cerebral cortex-derived tissues. Moreover, three clusters of PD patient cohorts were identified based on perturbed metabolic processes in the SN - each characterised by perturbations in (a) bile acid metabolism (b) omega-3 fatty acid metabolism, and (c) lipoic acid and androgen metabolism - metabolic themes not comprehensively addressed in PD. These perturbations were supported by concurrence between transcriptome and proteome changes in the expression patterns for CBR1, ECI2, BDH2, CYP27A1, ALDH1B1, ALDH9A1, ADH5, ALDH7A1, L1CAM, and PLXNB3 genes, providing a valuable resource for drug targeting and diagnosis. Also, we analysed 58 PD-control transcriptome data comparisons from in vivo/in vitro disease models and identified experimental PD models with significant correlations to matched human brain regions. Collectively, our findings suggest metabolic alterations in several brain regions, heterogeneity in metabolic alterations between study cohorts for the SN tissues and the need to optimize current experimental models to advance research on metabolic aspects of PD.

A transcriptome based approach to predict candidate drug targets and drugs for Parkinson's disease using an in vitro 6-OHDA model.

The most common treatment strategies for Parkinson's disease (PD) aim to slow down the neurodegeneration process or control the symptoms. In this study, using an in vitro PD model we carried out a transcriptome-based drug target prediction strategy. We identified novel drug target candidates by mapping genes upregulated in 6-OHDA-treated cells on a human protein-protein interaction network. Among the predicted targets, we show that AKR1C3 and CEBPB are promising in validating our bioinformatics approach since their known ligands, rutin and quercetin, respectively, act as neuroprotective drugs that effectively decrease cell death, and restore the expression profiles of key genes upregulated in 6-OHDA-treated cells. We also show that these two genes upregulated in our in vitro PD model are downregulated to basal levels upon drug administration. As a further validation of our methodology, we further confirm that the potential target genes identified with our bioinformatics approach are also upregulated in post-mortem transcriptome samples of PD patients from the literature. Therefore, we propose that this methodology predicts novel drug targets AKR1C3 and CEBPB, which are relevant to future clinical applications as potential drug repurposing targets for PD. Our systems-based computational approach to predict candidate drug targets can be employed in identifying novel drug targets in other diseases without a priori assumption.

Computational Approaches to Assess Abnormal Metabolism in Alzheimer's Disease Using Transcriptomics.

Transcriptome-integrated human genome-scale metabolic models (GEMs) have been used widely to assess alterations in metabolism in response to disease. Transcriptome integration leads to identification of metabolic reactions that are differentially inactivated in the tissue of interest. Among the methods available for mapping transcriptome data on GEMs, we focus here on an Integrative Metabolic Analysis Tool (iMAT), which we have recently applied to the analysis of Alzheimer's disease (AD). We provide a detailed protocol for applying iMAT to create models of personalized metabolic networks, which can be further processed to identify reactions associated with abnormal metabolism.

Six potential biomarkers for bladder cancer: key proteins in cell-cycle division and apoptosis pathways.

BACKGROUND: The bladder cancer (BC) pathology is caused by both exogenous environmental and endogenous molecular factors. Several genes have been implicated, but the molecular pathogenesis of BC and its subtypes remains debatable. The bioinformatic analysis evaluates high numbers of proteins in a single study, increasing the opportunity to identify possible biomarkers for disorders. METHODS: The aim of this study is to identify biomarkers for the identification of BC using several bioinformatic analytical tools and methods. BC and normal samples were compared for each probeset with T test in GSE13507 and GSE37817 datasets, and statistical probesets were verified with GSE52519 and E-MTAB-1940 datasets. Differential gene expression, hierarchical clustering, gene ontology enrichment analysis, and heuristic online phenotype prediction algorithm methods were utilized. Statistically significant proteins were assessed in the Human Protein Atlas database. GSE13507 (6271 probesets) and GSE37817 (3267 probesets) data were significant after the extraction of probesets without gene annotation information. Common probesets in both datasets (2888) were further narrowed by analyzing the first 100 upregulated and downregulated probesets in BC samples. RESULTS: Among the total 400 probesets, 68 were significant for both datasets with similar fold-change values (Pearson r: 0.995). Protein-protein interaction networks demonstrated strong interactions between CCNB1, BUB1B, and AURKB. The HPA database revealed similar protein expression levels for CKAP2L, AURKB, APIP, and LGALS3 both for BC and control samples. CONCLUSION: This study disclosed six candidate biomarkers for the early diagnosis of BC. It is suggested that these candidate proteins be investigated in a wet lab to identify their functions in BC pathology and possible treatment approaches.

Genome-Wide Analysis of Yeast Metabolic Cycle through Metabolic Network Models Reveals Superiority of Integrated ATAC-seq Data over RNA-seq Data.

Saccharomyces cerevisiae undergoes robust oscillations to regulate its physiology for adaptation and survival under nutrient-limited conditions. Environmental cues can induce rhythmic metabolic alterations in order to facilitate the coordination of dynamic metabolic behaviors. Of such metabolic processes, the yeast metabolic cycle enables adaptation of the cells to varying nutritional status through oscillations in gene expression and metabolite production levels. In this process, yeast metabolism is altered between diverse cellular states based on changing oxygen consumption levels: quiescent (reductive charging [RC]), growth (oxidative [OX]), and proliferation (reductive building [RB]) phases. We characterized metabolic alterations during the yeast metabolic cycle using a variety of approaches. Gene expression levels are widely used for condition-specific metabolic simulations, whereas the use of epigenetic information in metabolic modeling is still limited despite the clear relationship between epigenetics and metabolism. This prompted us to investigate the contribution of epigenomic information to metabolic predictions for progression of the yeast metabolic cycle. In this regard, we determined altered pathways through the prediction of regulated reactions and corresponding model genes relying on differential chromatin accessibility levels. The predicted metabolic alterations were confirmed via data analysis and literature. We subsequently utilized RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) data sets in the contextualization of the yeast model. The use of ATAC-seq data considerably enhanced the predictive capability of the model. To the best of our knowledge, this is the first attempt to use genome-wide chromatin accessibility data in metabolic modeling. The preliminary results showed that epigenomic data sets can pave the way for more accurate metabolic simulations. IMPORTANCE Dynamic chromatin organization mediates the emergence of condition-specific phenotypes in eukaryotic organisms. Saccharomyces cerevisiae can alter its metabolic profile via regulation of genome accessibility and robust transcriptional oscillations under nutrient-limited conditions. Thus, both epigenetic information and transcriptomic information are crucial in the understanding of condition-specific metabolic behavior in this organism. Based on genome-wide alterations in chromatin accessibility and transcription, we investigated the yeast metabolic cycle, which is a remarkable example of coordinated and dynamic yeast behavior. In this regard, we assessed the use of ATAC-seq and RNA-seq data sets in condition-specific metabolic modeling. To our knowledge, this is the first attempt to use chromatin accessibility data in the reconstruction of context-specific metabolic models, despite the extensive use of transcriptomic data. As a result of comparative analyses, we propose that the incorporation of epigenetic information is a promising approach in the accurate prediction of metabolic dynamics.

Dual transcriptome based reconstruction of Salmonella-human integrated metabolic network to screen potential drug targets.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a highly adaptive pathogenic bacteria with a serious public health concern due to its increasing resistance to antibiotics. Therefore, identification of novel drug targets for S. Typhimurium is crucial. Here, we first created a pathogen-host integrated genome-scale metabolic network by combining the metabolic models of human and S. Typhimurium, which we further tailored to the pathogenic state by the integration of dual transcriptome data. The integrated metabolic model enabled simultaneous investigation of metabolic alterations in human cells and S. Typhimurium during infection. Then, we used the tailored pathogen-host integrated genome-scale metabolic network to predict essential genes in the pathogen, which are candidate novel drug targets to inhibit infection. Drug target prioritization procedure was applied to these targets, and pabB was chosen as a putative drug target. It has an essential role in 4-aminobenzoic acid (PABA) synthesis, which is an essential biomolecule for many pathogens. A structure based virtual screening was applied through docking simulations to predict candidate compounds that eliminate S. Typhimurium infection by inhibiting pabB. To our knowledge, this is the first comprehensive study for predicting drug targets and drug like molecules by using pathogen-host integrated genome-scale models, dual RNA-seq data and structure-based virtual screening protocols. This framework will be useful in proposing novel drug targets and drugs for antibiotic-resistant pathogens.

Cancer Recurrence and Omics: Metabolic Signatures of Cancer Dormancy Revealed by Transcriptome Mapping of Genome-Scale Networks.

A major problem in medicine and oncology is cancer recurrence through the activation of dormant cancer cells. A system scale examination of metabolic dysregulations associated with the cancer dormancy offers promise for the discovery of novel molecular targets for cancer precision medicine, and importantly, for the prevention of cancer recurrence. In this study, we mapped the total mRNA sequencing-based transcriptomic data from dormant cancer cell lines and nondormant cancer controls onto a human genome-scale metabolic network by using a graph-based approach, and two mass balance-based approaches with one based on reaction activity/inactivity and the other one on flux changes. The gene expression datasets were accessed from Gene Expression Omnibus (GSE83142 and GSE114012). This analysis included two diverse cancer types, a liquid and a solid cancer, namely, acute lymphoblastic leukemia and colorectal cancer. For the dormant cancer state, we observed changes in major adenosine triphosphate-producing pathways, including the citric acid cycle, oxidative phosphorylation, and glycolysis/gluconeogenesis, indicating a reprogramming in the metabolism of dormant cells away from Warburg-based energy metabolism. All three computational approaches unanimously predicted that folate metabolism, pyruvate metabolism, and glutamate metabolism, as well as valine/leucine/isoleucine metabolism are likely dysregulated in cancer dormancy. These findings provide new insights and molecular pathway targets on cancer dormancy, comprehensively catalog dormancy-associated metabolic pathways, and inform future research aimed at prevention of cancer recurrence in particular.

A co-expression network based molecular characterization of genes responsive for Braak stages in Parkinson's disease.

The progression of Parkinson's disease (PD) is defined by six Braak stages. We used transcriptome data from PD patients with Braak stage information to understand underlying molecular mechanisms for the progress of the disease. We created networks of genes with continuously decreased/increased co-expression from control group to Braak 5-6 stages. These networks are significantly associated with PD-related mechanisms such as mitochondrial dysfunction and synaptic signalling among others. Applying weighted gene co-expression network analysis (WGCNA) algorithm to the co-expression networks led to more specific modules enriched with neurodegeneration-related disease pathways, seizure, abnormality of coordination, and hypotonia. Furthermore, we showed that one of the co-expression networks is clustered into three major communities with dedicated molecular functions: (i) tubulin folding pathway, gap junction-related mechanisms, neuronal system; (ii) synaptic vesicle, intracellular vesicle, proteasome complex, PD genes; (iii) energy metabolism, mitochondrial mechanisms, oxidative phosphorylation, TCA cycle, PD genes. The co-expression relations we identified in this study as crucial players in the disease progression cover several known PD-associated genes and genes whose products are known to physically interact with alpha-synuclein protein.

Further delineation of familial polycystic ovary syndrome (PCOS) via whole-exome sequencing: PCOS-related rare FBN3 and FN1 gene variants are identified.

AIM: To identify pathogenic rare coding Mendelian/high-effect size variant(s) by whole-exome sequencing in familial polycystic ovary syndrome (PCOS) patients to elucidate PCOS-related pathways. METHODS: Twenty women and their affected available relatives diagnosed with PCOS according to Rotterdam criteria were recruited. Whole-exome sequencing on germ-line DNA from 31 PCOS probands and their affected relatives was performed. Whole-exome sequencing data were further evaluated by pathway and chemogenomics analyses. In-slico analysis of candidate variants were done by VarCards for functional predictions and VarSite for impact on three-dimensional (3D) structures in the candidate proteins. RESULTS: Two heterozygous rare FBN3 missense variants in three patients, and one FN1 missense variant in one patient from three different PCOS families were identified. CONCLUSION: We identified three novel FBN3 and FN1 variants for the first time in the literature and linked with PCOS. Further functional studies may identify causality of these newly discovered PCOS-related variants, and their role yet remains to be investigated. Our findings may improve our understanding of the biological pathways affected and identify new drug targets.

Systematic investigation of mouse models of Parkinson's disease by transcriptome mapping on a brain-specific genome-scale metabolic network.

Genome-scale metabolic networks enable systemic investigation of metabolic alterations caused by diseases by providing interpretation of omics data. Although Mus musculus (mouse) is one of the most commonly used model organisms for neurodegenerative diseases, a brain-specific metabolic network model of mice has not yet been reconstructed. Here we reconstructed the first brain-specific metabolic network model of mice, iBrain674-Mm, by a homology-based approach, which consisted of 992 reactions controlled by 674 genes and distributed over 48 pathways. We validated the newly reconstructed network model by showing that it predicts healthy resting-state metabolic phenotypes of mouse brain compatible with the literature. We later used iBrain674-Mm to interpret various experimental mouse models of Parkinson's Disease (PD) at the transcriptome level. To this end, we applied a constraint-based modelling based biomarker prediction method called TIMBR (Transcriptionally Inferred Metabolic Biomarker Response) to predict altered metabolite production from transcriptomic data. Systemic analysis of seven different PD mouse models by TIMBR showed that the neuronal levels of glutamate, lactate, creatine phosphate, neuronal acetylcholine, bilirubin and formate increased in most of the PD mouse models, whereas the levels of melatonin, epinephrine, astrocytic formate and astrocytic bilirubin decreased. Although most of the predictions were consistent with the literature, there were some inconsistencies among different PD mouse models, signifying that there is no perfect experimental model to reflect PD metabolism. The newly reconstructed brain-specific genome-scale metabolic network model of mice can make important contributions to the interpretation and development of experimental mouse models of PD and other neurodegenerative diseases.

Transcriptional landscape of cellular networks reveal interactions driving the dormancy mechanisms in cancer.

Primary cancer cells exert unique capacity to disseminate and nestle in distant organs. Once seeded in secondary sites, cancer cells may enter a dormant state, becoming resistant to current treatment approaches, and they remain silent until they reactivate and cause overt metastases. To illuminate the complex mechanisms of cancer dormancy, 10 transcriptomic datasets from the literature enabling 21 dormancy-cancer comparisons were mapped on protein-protein interaction networks and gene-regulatory networks to extract subnetworks that are enriched in significantly deregulated genes. The genes appearing in the subnetworks and significantly upregulated in dormancy with respect to proliferative state were scored and filtered across all comparisons, leading to a dormancy-interaction network for the first time in the literature, which includes 139 genes and 1974 interactions. The dormancy interaction network will contribute to the elucidation of cellular mechanisms orchestrating cancer dormancy, paving the way for improvements in the diagnosis and treatment of metastatic cancer.

A systems pharmacology approach based on oncogenic signalling pathways to determine the mechanisms of action of natural products in breast cancer from transcriptome data.

BACKGROUND: Narrow spectrum of action through limited molecular targets and unforeseen drug-related toxicities have been the main reasons for drug failures at the phase I clinical trials in complex diseases. Most plant-derived compounds with medicinal values possess poly-pharmacologic properties with overall good tolerability, and, thus, are appropriate in the management of complex diseases, especially cancers. However, methodological limitations impede attempts to catalogue targeted processes and infer systemic mechanisms of action. While most of the current understanding of these compounds is based on reductive methods, it is increasingly becoming clear that holistic techniques, leveraging current improvements in omic data collection and bioinformatics methods, are better suited for elucidating their systemic effects. Thus, we developed and implemented an integrative systems biology pipeline to study these compounds and reveal their mechanism of actions on breast cancer cell lines. METHODS: Transcriptome data from compound-treated breast cancer cell lines, representing triple negative (TN), luminal A (ER+) and HER2+ tumour types, were mapped on human protein interactome to construct targeted subnetworks. The subnetworks were analysed for enriched oncogenic signalling pathways. Pathway redundancy was reduced by constructing pathway-pathway interaction networks, and the sets of overlapping genes were subsequently used to infer pathway crosstalk. The resulting filtered pathways were mapped on oncogenesis processes to evaluate their anti-carcinogenic effectiveness, and thus putative mechanisms of action. RESULTS: The signalling pathways regulated by Actein, Withaferin A, Indole-3-Carbinol and Compound Kushen, which are extensively researched compounds, were shown to be projected on a set of oncogenesis processes at the transcriptomic level in different breast cancer subtypes. The enrichment of well-known tumour driving genes indicate that these compounds indirectly dysregulate cancer driving pathways in the subnetworks. CONCLUSION: The proposed framework infers the mechanisms of action of potential drug candidates from their enriched protein interaction subnetworks and oncogenic signalling pathways. It also provides a systematic approach for evaluating such compounds in polygenic complex diseases. In addition, the plant-based compounds used here show poly-pharmacologic mechanism of action by targeting subnetworks enriched with cancer driving genes. This network perspective supports the need for a systemic drug-target evaluation for lead compounds prior to efficacy experiments.

Working together.

Heart attacks have a ripple effect on how other organs exchange biomolecules that help the heart respond to injury.

Abnormal brain cholesterol homeostasis in Alzheimer's disease-a targeted metabolomic and transcriptomic study.

The role of brain cholesterol metabolism in Alzheimer's disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson's disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.