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  1. Article ; Online: Evaluation of Na

    Martinowich, Keri / Das, Debamitra / Sripathy, Srinidhi Rao / Mai, Yishan / Kenney, Rakaia F / Maher, Brady J

    Molecular psychiatry

    2022  Volume 28, Issue 1, Page(s) 76–82

    Abstract: Pitt Hopkins Syndrome (PTHS) is a rare syndromic form of autism spectrum disorder (ASD) caused by autosomal dominant mutations in the Transcription Factor 4 (TCF4) gene. TCF4 is a basic helix-loop-helix transcription factor that is critical for ... ...

    Abstract Pitt Hopkins Syndrome (PTHS) is a rare syndromic form of autism spectrum disorder (ASD) caused by autosomal dominant mutations in the Transcription Factor 4 (TCF4) gene. TCF4 is a basic helix-loop-helix transcription factor that is critical for neurodevelopment and brain function through its binding to cis-regulatory elements of target genes. One potential therapeutic strategy for PTHS is to identify dysregulated target genes and normalize their dysfunction. Here, we propose that SCN10A is an important target gene of TCF4 that is an applicable therapeutic approach for PTHS. Scn10a encodes the voltage-gated sodium channel Na
    MeSH term(s) Animals ; Mice ; Autism Spectrum Disorder/drug therapy ; Autism Spectrum Disorder/genetics ; Autism Spectrum Disorder/metabolism ; Facies ; Hyperventilation/genetics ; Intellectual Disability/drug therapy ; Intellectual Disability/genetics ; Intellectual Disability/metabolism ; Transcription Factor 4/genetics ; NAV1.8 Voltage-Gated Sodium Channel/chemistry ; NAV1.8 Voltage-Gated Sodium Channel/metabolism
    Chemical Substances Transcription Factor 4 ; Scn10a protein, mouse ; NAV1.8 Voltage-Gated Sodium Channel
    Language English
    Publishing date 2022-10-12
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-022-01811-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4812: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt-Hopkins syndrome.

    Bohlen, Joseph F / Cleary, Colin M / Das, Debamitra / Sripathy, Srinidhi Rao / Sadowski, Norah / Shim, Gina / Kenney, Rakaia F / Buchler, Ingrid P / Banerji, Tapasree / Scanlan, Thomas S / Mulkey, Daniel K / Maher, Brady J

    Brain : a journal of neurology

    2023  Volume 146, Issue 8, Page(s) 3331–3346

    Abstract: Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and ...

    Abstract Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt-Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt-Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt-Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.
    MeSH term(s) Humans ; Animals ; Mice ; Clemastine ; Autism Spectrum Disorder/drug therapy ; Autism Spectrum Disorder/genetics ; Pharmaceutical Preparations ; Intellectual Disability/drug therapy ; Intellectual Disability/genetics
    Chemical Substances GC 1 compound ; Clemastine (95QN29S1ID) ; Pharmaceutical Preparations
    Language English
    Publishing date 2023-05-09
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awad057
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui II Zs.26: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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