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Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners

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@article{e822fe7314ab47fd9a23bfdcb75fa191,
title = "Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners",
abstract = "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.",
keywords = "Disks Large Homolog 4 Protein/genetics, Humans, Intellectual Disability/metabolism, Neurodevelopmental Disorders/genetics, Phenotype, Post-Synaptic Density/metabolism, Synapses/metabolism",
author = "Levy, {Amanda M} and Paulino Gomez-Puertas and Zeynep T{\"u}mer",
year = "2022",
month = apr,
day = "15",
doi = "10.3390/ijms23084390",
language = "English",
volume = "23",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Molecular Diversity Preservation International (M D P I)",
number = "8",

}

RIS

TY - JOUR

T1 - Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners

AU - Levy, Amanda M

AU - Gomez-Puertas, Paulino

AU - Tümer, Zeynep

PY - 2022/4/15

Y1 - 2022/4/15

N2 - 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.

AB - 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.

KW - Disks Large Homolog 4 Protein/genetics

KW - Humans

KW - Intellectual Disability/metabolism

KW - Neurodevelopmental Disorders/genetics

KW - Phenotype

KW - Post-Synaptic Density/metabolism

KW - Synapses/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85128199795&partnerID=8YFLogxK

U2 - 10.3390/ijms23084390

DO - 10.3390/ijms23084390

M3 - Review

C2 - 35457207

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 8

M1 - 4390

ER -

ID: 77927771