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  1. Article ; Online: Interleukin-6 deficiency exacerbates Huntington's disease model phenotypes.

    Wertz, Mary H / Pineda, S Sebastian / Lee, Hyeseung / Kulicke, Ruth / Kellis, Manolis / Heiman, Myriam

    Molecular neurodegeneration

    2020  Volume 15, Issue 1, Page(s) 29

    Abstract: Huntington's disease (HD) is an incurable neurodegenerative disorder caused by CAG trinucleotide expansions in the huntingtin gene. Markers of both systemic and CNS immune activation and inflammation have been widely noted in HD and mouse models of HD. ... ...

    Abstract Huntington's disease (HD) is an incurable neurodegenerative disorder caused by CAG trinucleotide expansions in the huntingtin gene. Markers of both systemic and CNS immune activation and inflammation have been widely noted in HD and mouse models of HD. In particular, elevation of the pro-inflammatory cytokine interleukin-6 (IL-6) is the earliest reported marker of immune activation in HD, and this elevation has been suggested to contribute to HD pathogenesis. To test the hypothesis that IL-6 deficiency would be protective against the effects of mutant huntingtin, we generated R6/2 HD model mice that lacked IL-6. Contrary to our prediction, IL-6 deficiency exacerbated HD-model associated behavioral phenotypes. Single nuclear RNA Sequencing (snRNA-seq) analysis of striatal cell types revealed that IL-6 deficiency led to the dysregulation of various genes associated with synaptic function, as well as the BDNF receptor Ntrk2. These data suggest that IL-6 deficiency exacerbates the effects of mutant huntingtin through dysregulation of genes of known relevance to HD pathobiology in striatal neurons, and further suggest that modulation of IL-6 to a level that promotes proper regulation of genes associated with synaptic function may hold promise as an HD therapeutic target.
    MeSH term(s) Animals ; Brain/metabolism ; Brain/physiopathology ; Corpus Striatum/metabolism ; Disease Models, Animal ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Interleukin-6/deficiency ; Interleukin-6/metabolism ; Mice, Transgenic ; Phenotype
    Chemical Substances Interleukin-6
    Language English
    Publishing date 2020-05-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2244557-2
    ISSN 1750-1326 ; 1750-1326
    ISSN (online) 1750-1326
    ISSN 1750-1326
    DOI 10.1186/s13024-020-00379-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.

    Pineda, S Sebastian / Lee, Hyeseung / Ulloa-Navas, Maria J / Linville, Raleigh M / Garcia, Francisco J / Galani, Kyriakitsa / Engelberg-Cook, Erica / Castanedes, Monica C / Fitzwalter, Brent E / Pregent, Luc J / Gardashli, Mahammad E / DeTure, Michael / Vera-Garcia, Diana V / Hucke, Andre T S / Oskarsson, Bjorn E / Murray, Melissa E / Dickson, Dennis W / Heiman, Myriam / Belzil, Veronique V /
    Kellis, Manolis

    Cell

    2024  Volume 187, Issue 8, Page(s) 1971–1989.e16

    Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types ... ...

    Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.
    MeSH term(s) Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Frontotemporal Dementia/genetics ; Frontotemporal Lobar Degeneration/genetics ; Frontotemporal Lobar Degeneration/metabolism ; Frontotemporal Lobar Degeneration/pathology ; Gene Expression Profiling ; Neurons/metabolism ; Prefrontal Cortex/metabolism ; Prefrontal Cortex/pathology ; Single-Cell Gene Expression Analysis
    Language English
    Publishing date 2024-03-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2024.02.031
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1167: Show issues Location:
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  3. Article ; Online: A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane.

    Guillén-Samander, Andrés / Wu, Yumei / Pineda, S Sebastian / García, Francisco J / Eisen, Julia N / Leonzino, Marianna / Ugur, Berrak / Kellis, Manolis / Heiman, Myriam / De Camilli, Pietro

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 35, Page(s) e2205425119

    Abstract: Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally ... ...

    Abstract Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of plasma membrane (PM) lipid scramblases whose action results in exposure of PtdSer at the cell surface. VPS13A is an endoplasmic reticulum (ER)-anchored lipid transfer protein with a putative role in the transport of lipids at contacts of the ER with other membranes. Recently VPS13A and XK were reported to interact by still unknown mechanisms. So far, however, there is no evidence for a colocalization of the two proteins at contacts of the ER with the PM, where XK resides, as VPS13A was shown to be localized at contacts between the ER and either mitochondria or lipid droplets. Here we show that VPS13A can also localize at ER-PM contacts via the binding of its PH domain to a cytosolic loop of XK, that such interaction is regulated by an intramolecular interaction within XK, and that both VPS13A and XK are highly expressed in the caudate neurons. Binding of the PH domain of VPS13A to XK is competitive with its binding to intracellular membranes that mediate other tethering functions of VPS13A. Our findings support a model according to which VPS13A-dependent lipid transfer between the ER and the PM is coupled to lipid scrambling within the PM. They raise the possibility that defective cell surface exposure of PtdSer may be responsible for neurodegeneration.
    MeSH term(s) Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Membrane/metabolism ; Endoplasmic Reticulum/enzymology ; Endoplasmic Reticulum/metabolism ; Humans ; Lipids ; Neuroacanthocytosis/metabolism ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism
    Chemical Substances Carrier Proteins ; Lipids ; VPS13A protein, human ; Vesicular Transport Proteins
    Language English
    Publishing date 2022-08-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2205425119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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  4. Article ; Online: Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation.

    Lee, Hyeseung / Fenster, Robert J / Pineda, S Sebastian / Gibbs, Whitney S / Mohammadi, Shahin / Davila-Velderrain, Jose / Garcia, Francisco J / Therrien, Martine / Novis, Hailey S / Gao, Fan / Wilkinson, Hilary / Vogt, Thomas / Kellis, Manolis / LaVoie, Matthew J / Heiman, Myriam

    Neuron

    2020  Volume 107, Issue 5, Page(s) 891–908.e8

    Abstract: The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington's disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity ... ...

    Abstract The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington's disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.
    MeSH term(s) Animals ; Humans ; Huntingtin Protein/genetics ; Huntingtin Protein/immunology ; Huntington Disease/genetics ; Huntington Disease/immunology ; Huntington Disease/pathology ; Immunity, Innate/immunology ; Mice ; Mutation ; Neurons/immunology ; Neurons/pathology ; RNA, Mitochondrial/immunology ; Transcriptome
    Chemical Substances Huntingtin Protein ; RNA, Mitochondrial
    Language English
    Publishing date 2020-07-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2020.06.021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2496: Show issues Location:
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    Zs.MG 92: Show issues

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  5. Article ; Online: Genome-wide In Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity.

    Wertz, Mary H / Mitchem, Mollie R / Pineda, S Sebastian / Hachigian, Lea J / Lee, Hyeseung / Lau, Vanessa / Powers, Alex / Kulicke, Ruth / Madan, Gurrein K / Colic, Medina / Therrien, Martine / Vernon, Amanda / Beja-Glasser, Victoria F / Hegde, Mudra / Gao, Fan / Kellis, Manolis / Hart, Traver / Doench, John G / Heiman, Myriam

    Neuron

    2020  Volume 106, Issue 1, Page(s) 76–89.e8

    Abstract: Unbiased in vivo genome-wide genetic screening is a powerful approach to elucidate new molecular mechanisms, but such screening has not been possible to perform in the mammalian central nervous system (CNS). Here, we report the results of the first ... ...

    Abstract Unbiased in vivo genome-wide genetic screening is a powerful approach to elucidate new molecular mechanisms, but such screening has not been possible to perform in the mammalian central nervous system (CNS). Here, we report the results of the first genome-wide genetic screens in the CNS using both short hairpin RNA (shRNA) and CRISPR libraries. Our screens identify many classes of CNS neuronal essential genes and demonstrate that CNS neurons are particularly sensitive not only to perturbations to synaptic processes but also autophagy, proteostasis, mRNA processing, and mitochondrial function. These results reveal a molecular logic for the common implication of these pathways across multiple neurodegenerative diseases. To further identify disease-relevant genetic modifiers, we applied our screening approach to two mouse models of Huntington's disease (HD). Top mutant huntingtin toxicity modifier genes included several Nme genes and several genes involved in methylation-dependent chromatin silencing and dopamine signaling, results that reveal new HD therapeutic target pathways.
    MeSH term(s) Animals ; Behavior, Animal ; CRISPR-Cas Systems ; Cell Survival/genetics ; Gene Knockdown Techniques ; Gene Library ; Genes, Essential/genetics ; Huntingtin Protein/genetics ; Huntington Disease/genetics ; Mice ; Mice, Transgenic ; NM23 Nucleoside Diphosphate Kinases/genetics ; Neostriatum/metabolism ; Neurons/metabolism ; Nucleoside Diphosphate Kinase D/genetics ; Protein Aggregates ; RNA Interference ; RNA, Guide, CRISPR-Cas Systems ; RNA, Small Interfering ; Receptors, Dopamine D2/genetics ; Sequence Analysis, RNA
    Chemical Substances DRD2 protein, mouse ; HTT protein, human ; Huntingtin Protein ; NM23 Nucleoside Diphosphate Kinases ; Protein Aggregates ; RNA, Guide, CRISPR-Cas Systems ; RNA, Small Interfering ; Receptors, Dopamine D2 ; Nme1 protein, mouse (EC 2.7.4.6) ; Nme3 protein, mouse (EC 2.7.4.6) ; Nme4 protein, mouse (EC 2.7.4.6) ; Nucleoside Diphosphate Kinase D (EC 2.7.4.6)
    Language English
    Publishing date 2020-01-30
    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 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2020.01.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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