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| Home > Publications Database > Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium. |
| Home > Publications Database > Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium. |
| Journal Article | DZNE-2024-00739 |
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2024
Macmillan
London
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Please use a persistent id in citations: doi:10.1038/s41380-023-02362-y
Abstract: The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(-/-) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(-/-) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(-/-) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(-/-) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.
Keyword(s): Animals (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; Nerve Tissue Proteins: metabolism (MeSH) ; Hippocampus: metabolism (MeSH) ; Extracellular Matrix: metabolism (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; beta Catenin: metabolism (MeSH) ; beta Catenin: genetics (MeSH) ; Chromosome Disorders: genetics (MeSH) ; Chromosome Disorders: metabolism (MeSH) ; Chromosome Deletion (MeSH) ; Cell Cycle: drug effects (MeSH) ; Cell Cycle: genetics (MeSH) ; Autistic Disorder: genetics (MeSH) ; Autistic Disorder: metabolism (MeSH) ; Chromosomes, Human, Pair 22: genetics (MeSH) ; Cyclic AMP Response Element-Binding Protein: metabolism (MeSH) ; Cyclic AMP Response Element-Binding Protein: genetics (MeSH) ; Male (MeSH) ; Transcriptome: genetics (MeSH) ; Autism Spectrum Disorder: genetics (MeSH) ; Autism Spectrum Disorder: metabolism (MeSH) ; Autism Spectrum Disorder: drug therapy (MeSH) ; Mice, Inbred C57BL (MeSH) ; Lithium: pharmacology (MeSH) ; Microfilament Proteins: metabolism (MeSH) ; Microfilament Proteins: genetics (MeSH) ; Cells, Cultured (MeSH) ; Shank3 protein, mouse ; Nerve Tissue Proteins ; beta Catenin ; Creb1 protein, mouse ; Cyclic AMP Response Element-Binding Protein ; CTNNB1 protein, mouse ; Lithium ; Microfilament Proteins
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