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1.
Mol Psychiatry ; 28(5): 2122-2135, 2023 05.
Article in English | MEDLINE | ID: mdl-36782060

ABSTRACT

MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.


Subject(s)
Autism Spectrum Disorder , Animals , Humans , Mice , Autism Spectrum Disorder/drug therapy , Autism Spectrum Disorder/genetics , Autistic Disorder/drug therapy , Autistic Disorder/genetics , Haploinsufficiency/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Phenotype , Transcription Factors/genetics
2.
J Immunol ; 206(8): 1697-1708, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33731337

ABSTRACT

The prime function of proteasomes is the control of protein homeostasis in cells (i.e., the removal of proteins that are not properly folded, damaged by stress conditions like reactive oxygen species formation, or degraded on the basis of regular protein turnover). During viral infection, the standard proteasome is replaced by the so-called immunoproteasome (IP) in an IFN-γ-dependent manner. It has been proposed that the IP is required to protect cell viability under conditions of IFN-induced oxidative stress. In this study, we investigated the requirement for IP to cope with the enhanced need for protein degradation during lymphocytic choriomeningitis virus (LCMV) infection in mice lacking the IP subunit LMP7. We found that IP are upregulated in the liver but not in the spleen during LCMV infection, although the total proteasome content was not altered. The expression of standard proteasome subunits is not induced in LMP7-deficient mice, indicating that enhanced proteasomal activity is not required during viral infection. Furthermore, ubiquitin accumulation, apoptosis induction, and viral titers were similar in LCMV-infected mice lacking LMP7 compared with wild-type mice. Taken together, these data indicate that the IP is not required to regulate protein homeostasis during LCMV infection.


Subject(s)
Lymphocytic Choriomeningitis/immunology , Lymphocytic choriomeningitis virus/physiology , Proteasome Endopeptidase Complex/metabolism , T-Lymphocytes/immunology , Animals , Cells, Cultured , Homeostasis , Interferon-gamma/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Proteasome Endopeptidase Complex/genetics , Proteolysis , Up-Regulation
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