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  1. Article ; Online: NREM delta power and AD-relevant tauopathy are associated with shared cortical gene networks.

    Scarpa, Joseph R / Jiang, Peng / Gao, Vance D / Vitaterna, Martha H / Turek, Fred W / Kasarskis, Andrew

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 7797

    Abstract: Reduced NREM sleep in humans is associated with AD neuropathology. Recent work has demonstrated a reduction in NREM sleep in preclinical AD, pointing to its potential utility as an early marker of dementia. We test the hypothesis that reduced NREM delta ... ...

    Abstract Reduced NREM sleep in humans is associated with AD neuropathology. Recent work has demonstrated a reduction in NREM sleep in preclinical AD, pointing to its potential utility as an early marker of dementia. We test the hypothesis that reduced NREM delta power and increased tauopathy are associated with shared underlying cortical molecular networks in preclinical AD. We integrate multi-omics data from two extensive public resources, a human Alzheimer's disease cohort from the Mount Sinai Brain Bank (N = 125) reflecting AD progression and a (C57BL/6J × 129S1/SvImJ) F2 mouse population in which NREM delta power was measured (N = 98). Two cortical gene networks, including a CLOCK-dependent circadian network, are associated with NREM delta power and AD tauopathy progression. These networks were validated in independent mouse and human cohorts. Identifying gene networks related to preclinical AD elucidate possible mechanisms associated with the early disease phase and potential targets to alter the disease course.
    MeSH term(s) Alzheimer Disease/pathology ; Animals ; Cerebellar Cortex/metabolism ; Cohort Studies ; Gene Regulatory Networks ; Humans ; Mice ; Mice, Inbred C57BL ; Sleep Wake Disorders/pathology
    Language English
    Publishing date 2021-04-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-86255-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Parkinson's Disease is Associated with Dysregulations of a Dopamine-Modulated Gene Network Relevant to Sleep and Affective Neurobehaviors in the Striatum.

    Jiang, Peng / Scarpa, Joseph R / Gao, Vance D / Vitaterna, Martha Hotz / Kasarskis, Andrew / Turek, Fred W

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 4808

    Abstract: In addition to the characteristic motor symptoms, Parkinson's disease (PD) often involves a constellation of sleep and mood symptoms. However, the mechanisms underlying these comorbidities are largely unknown. We have previously reconstructed gene ... ...

    Abstract In addition to the characteristic motor symptoms, Parkinson's disease (PD) often involves a constellation of sleep and mood symptoms. However, the mechanisms underlying these comorbidities are largely unknown. We have previously reconstructed gene networks in the striatum of a population of (C57BL/6J x A/J) F2 mice and associated the networks to sleep and affective phenotypes, providing a resource for integrated analyses to investigate perturbed sleep and affective functions at the gene network level. Combining this resource with PD-relevant transcriptomic datasets from humans and mice, we identified four networks that showed elevated gene expression in PD patients, including a circadian clock and mitotic network that was altered similarly in mouse models of PD. We then utilized multiple types of omics data from public databases and linked this gene network to postsynaptic dopamine signaling in the striatum, CDK1-modulated transcriptional regulation, and the genetic susceptibility of PD. These findings suggest that dopamine deficiency, a key aspect of PD pathology, perturbs a circadian/mitotic gene network in striatal neurons. Since the normal functions of this network were relevant to sleep and affective behaviors, these findings implicate that dysregulation of functional gene networks may be involved in the emergence of non-motor symptoms in PD. Our analyses present a framework for integrating multi-omics data from diverse sources in mice and humans to reveal insights into comorbid symptoms of complex diseases.
    MeSH term(s) Affective Symptoms/genetics ; Affective Symptoms/pathology ; Affective Symptoms/physiopathology ; Animals ; CDC2 Protein Kinase/metabolism ; Circadian Clocks/genetics ; Corpus Striatum/cytology ; Corpus Striatum/pathology ; Corpus Striatum/physiopathology ; Datasets as Topic ; Disease Models, Animal ; Dopamine/deficiency ; Dopaminergic Neurons/pathology ; Gene Expression Profiling ; Gene Expression Regulation/physiology ; Gene Regulatory Networks/physiology ; Genetic Predisposition to Disease ; Humans ; Male ; Mice ; Parkinson Disease/genetics ; Parkinson Disease/pathology ; Parkinson Disease/physiopathology ; Sleep/genetics ; Transcription, Genetic
    Chemical Substances CDC2 Protein Kinase (EC 2.7.11.22) ; CDK1 protein, human (EC 2.7.11.22) ; Cdk1 protein, mouse (EC 2.7.11.22) ; Dopamine (VTD58H1Z2X)
    Language English
    Publishing date 2019-03-18
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-41248-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Cross-species systems analysis identifies gene networks differentially altered by sleep loss and depression.

    Scarpa, Joseph R / Jiang, Peng / Gao, Vance D / Fitzpatrick, Karrie / Millstein, Joshua / Olker, Christopher / Gotter, Anthony / Winrow, Christopher J / Renger, John J / Kasarskis, Andrew / Turek, Fred W / Vitaterna, Martha H

    Science advances

    2018  Volume 4, Issue 7, Page(s) eaat1294

    Abstract: To understand the transcriptomic organization underlying sleep and affective function, we studied a population of (C57BL/6J × 129S1/SvImJ) F2 mice by measuring 283 affective and sleep phenotypes and profiling gene expression across four brain regions. We ...

    Abstract To understand the transcriptomic organization underlying sleep and affective function, we studied a population of (C57BL/6J × 129S1/SvImJ) F2 mice by measuring 283 affective and sleep phenotypes and profiling gene expression across four brain regions. We identified converging molecular bases for sleep and affective phenotypes at both the single-gene and gene-network levels. Using publicly available transcriptomic datasets collected from sleep-deprived mice and patients with major depressive disorder (MDD), we identified three cortical gene networks altered by the sleep/wake state and depression. The network-level actions of sleep loss and depression were opposite to each other, providing a mechanistic basis for the sleep disruptions commonly observed in depression, as well as the reported acute antidepressant effects of sleep deprivation. We highlight one particular network composed of circadian rhythm regulators and neuronal activity-dependent immediate-early genes. The key upstream driver of this network,
    MeSH term(s) Animals ; Antidepressive Agents/therapeutic use ; Brain/metabolism ; Cerebral Cortex/metabolism ; Circadian Rhythm/genetics ; Depressive Disorder, Major/drug therapy ; Depressive Disorder, Major/genetics ; Depressive Disorder, Major/pathology ; Disease Models, Animal ; Gene Regulatory Networks ; Genotype ; Male ; Mice ; Mice, Inbred C57BL ; Phenotype ; Quantitative Trait Loci ; Sleep Deprivation/drug therapy ; Sleep Deprivation/genetics ; Sleep Deprivation/pathology ; Transcriptome
    Chemical Substances Antidepressive Agents
    Language English
    Publishing date 2018-07-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.aat1294
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Systems Genetic Analyses Highlight a TGFβ-FOXO3 Dependent Striatal Astrocyte Network Conserved across Species and Associated with Stress, Sleep, and Huntington's Disease.

    Scarpa, Joseph R / Jiang, Peng / Losic, Bojan / Readhead, Ben / Gao, Vance D / Dudley, Joel T / Vitaterna, Martha H / Turek, Fred W / Kasarskis, Andrew

    PLoS genetics

    2016  Volume 12, Issue 7, Page(s) e1006137

    Abstract: Recent systems-based analyses have demonstrated that sleep and stress traits emerge from shared genetic and transcriptional networks, and clinical work has elucidated the emergence of sleep dysfunction and stress susceptibility as early symptoms of ... ...

    Abstract Recent systems-based analyses have demonstrated that sleep and stress traits emerge from shared genetic and transcriptional networks, and clinical work has elucidated the emergence of sleep dysfunction and stress susceptibility as early symptoms of Huntington's disease. Understanding the biological bases of these early non-motor symptoms may reveal therapeutic targets that prevent disease onset or slow disease progression, but the molecular mechanisms underlying this complex clinical presentation remain largely unknown. In the present work, we specifically examine the relationship between these psychiatric traits and Huntington's disease (HD) by identifying striatal transcriptional networks shared by HD, stress, and sleep phenotypes. First, we utilize a systems-based approach to examine a large publicly available human transcriptomic dataset for HD (GSE3790 from GEO) in a novel way. We use weighted gene coexpression network analysis and differential connectivity analyses to identify transcriptional networks dysregulated in HD, and we use an unbiased ranking scheme that leverages both gene- and network-level information to identify a novel astrocyte-specific network as most relevant to HD caudate. We validate this result in an independent HD cohort. Next, we computationally predict FOXO3 as a regulator of this network, and use multiple publicly available in vitro and in vivo experimental datasets to validate that this astrocyte HD network is downstream of a signaling pathway important in adult neurogenesis (TGFβ-FOXO3). We also map this HD-relevant caudate subnetwork to striatal transcriptional networks in a large (n = 100) chronically stressed (B6xA/J)F2 mouse population that has been extensively phenotyped (328 stress- and sleep-related measurements), and we show that this striatal astrocyte network is correlated to sleep and stress traits, many of which are known to be altered in HD cohorts. We identify causal regulators of this network through Bayesian network analysis, and we highlight their relevance to motor, mood, and sleep traits through multiple in silico approaches, including an examination of their protein binding partners. Finally, we show that these causal regulators may be therapeutically viable for HD because their downstream network was partially modulated by deep brain stimulation of the subthalamic nucleus, a medical intervention thought to confer some therapeutic benefit to HD patients. In conclusion, we show that an astrocyte transcriptional network is primarily associated to HD in the caudate and provide evidence for its relationship to molecular mechanisms of neural stem cell homeostasis. Furthermore, we present a unified systems-based framework for identifying gene networks that are associated with complex non-motor traits that manifest in the earliest phases of HD. By analyzing and integrating multiple independent datasets, we identify a point of molecular convergence between sleep, stress, and HD that reflects their phenotypic comorbidity and reveals a molecular pathway involved in HD progression.
    MeSH term(s) Animals ; Astrocytes/metabolism ; Astrocytes/pathology ; Corpus Striatum/metabolism ; Corpus Striatum/physiopathology ; Forkhead Box Protein O3/biosynthesis ; Forkhead Box Protein O3/genetics ; Gene Regulatory Networks ; Humans ; Huntington Disease/genetics ; Huntington Disease/physiopathology ; Mice ; Nerve Net/metabolism ; Nerve Net/pathology ; Neurogenesis/genetics ; Signal Transduction ; Sleep/genetics ; Stress, Psychological/genetics ; Stress, Psychological/metabolism ; Transcriptome/genetics ; Transforming Growth Factor beta/biosynthesis ; Transforming Growth Factor beta/genetics
    Chemical Substances Forkhead Box Protein O3 ; Transforming Growth Factor beta
    Language English
    Publishing date 2016-07-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1006137
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A systems approach identifies networks and genes linking sleep and stress: implications for neuropsychiatric disorders.

    Jiang, Peng / Scarpa, Joseph R / Fitzpatrick, Karrie / Losic, Bojan / Gao, Vance D / Hao, Ke / Summa, Keith C / Yang, He S / Zhang, Bin / Allada, Ravi / Vitaterna, Martha H / Turek, Fred W / Kasarskis, Andrew

    Cell reports

    2015  Volume 11, Issue 5, Page(s) 835–848

    Abstract: Sleep dysfunction and stress susceptibility are comorbid complex traits that often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multilevel organizations of genetic landscape, candidate genes, and ... ...

    Abstract Sleep dysfunction and stress susceptibility are comorbid complex traits that often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multilevel organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J × A/J) F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type-specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests that the interplay among sleep, stress, and neuropathology emerges from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework for interrogating the mechanisms underlying sleep, stress susceptibility, and related neuropsychiatric disorders.
    MeSH term(s) Animals ; Bayes Theorem ; Gene Regulatory Networks ; Mental Disorders/genetics ; Mental Disorders/pathology ; Mental Disorders/veterinary ; Mice, Inbred C57BL ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Phenotype ; Quantitative Trait Loci ; Sleep ; Stress, Psychological/genetics ; Transcriptome
    Chemical Substances Microfilament Proteins
    Language English
    Publishing date 2015-05-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2015.04.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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