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Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners

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The postsynaptic density (PSD) is a massive protein complex, critical for synaptic strength and plasticity in excitatory neurons. Here, the scaffolding protein PSD-95 plays a crucial role as it organizes key PSD components essential for synaptic signaling, development, and survival. Recently, variants in DLG4 encoding PSD-95 were found to cause a neurodevelopmental disorder with a variety of clinical features including intellectual disability, developmental delay, and epilepsy. Genetic variants in several of the interaction partners of PSD-95 are associated with similar phenotypes, suggesting that deficient PSD-95 may affect the interaction partners, explaining the overlapping symptoms. Here, we review the transmembrane interaction partners of PSD-95 and their association with neurodevelopmental disorders. We assess how the structural changes induced by DLG4 missense variants may disrupt or alter such protein-protein interactions, and we argue that the pathological effect of DLG4 variants is, at least partly, exerted indirectly through interaction partners of PSD-95. This review presents a direction for functional studies to elucidate the pathogenic mechanism of deficient PSD-95, providing clues for therapeutic strategies.

Original languageEnglish
Article number4390
JournalInternational Journal of Molecular Sciences
Volume23
Issue number8
ISSN1661-6596
DOIs
Publication statusPublished - 15 Apr 2022

    Research areas

  • Disks Large Homolog 4 Protein/genetics, Humans, Intellectual Disability/metabolism, Neurodevelopmental Disorders/genetics, Phenotype, Post-Synaptic Density/metabolism, Synapses/metabolism

ID: 77927771