DLG4 Protein (Discs Large Homolog 4 / PSD-95) <div class="infobox infobox-protein">
Overview DLG4 (Discs Large Homolog 4) , more commonly known as PSD-95 , is a core scaffold protein of the postsynaptic density that organizes excitatory synapses. The [DLG4](/genes/dlg4) gene encodes a 724-amino acid protein essential for synaptic structure, function, and plasticity.
Structure PSD-95 contains multiple protein-interaction domains:
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DLG4 Protein (Discs Large Homolog 4 / PSD-95) <div class="infobox infobox-protein">
Overview DLG4 (Discs Large Homolog 4) , more commonly known as PSD-95 , is a core scaffold protein of the postsynaptic density that organizes excitatory synapses. The [DLG4](/genes/dlg4) gene encodes a 724-amino acid protein essential for synaptic structure, function, and plasticity.
Structure PSD-95 contains multiple protein-interaction domains:
| Domain | Position | Function |
This modular architecture allows PSD-95 to assemble large signaling complexes at synapses.
Biological Function
Synaptic Scaffold PSD-95 organizes the postsynaptic density:
AMPA receptor anchoring : Regulates synaptic AMPA receptor trafficking[NMDA receptor](/entities/nmda-receptor) complex : Links NMDA receptors to downstream signalingK+ channel regulation : Associates with Kv1 channelsSignaling complex assembly : Recruits enzymes and effectors
Synaptic Plasticity PSD-95 is critical for learning and memory:
Regulates [long-term potentiation](/mechanisms/long-term-potentiation) (LTP)
Controls long-term depression (LTD)
Modulates spine morphology
Activity-dependent modifications
Protein Interactions Key PSD-95 interacting proteins:
GluA1-4 : AMPA receptor subunitsNR1, NR2A/B : NMDA receptor subunitsAKAP79/150 : A-kinase anchoring proteinsSynGAP : Ras GTPase-activating proteinnNOS : Neuronal nitric oxide synthaseRole in Neurodegeneration
Alzheimer's Disease PSD-95 alterations contribute to synaptic failure in AD:
Synaptic loss : Reduced PSD-95 expression in AD brainAβ toxicity : [Amyloid-beta](/proteins/amyloid-beta) disrupts PSD-95 interactions[Tau](/proteins/tau) pathology : Phosphorylated tau affects PSD-95 functionMemory deficits : Impaired synaptic plasticity
Parkinson's Disease
Dopaminergic synapses : PSD-95 in striatal medium spiny [neurons](/entities/neurons)Excitotoxicity : NMDA receptor dysregulationSynaptic pruning : Altered PSD-95 in disease modelsTherapeutic Potential Targeting PSD-95 interactions shows promise:
Neuroprotective peptides : Mimetic peptides preserving synapsesSmall molecule modulators : Stabilize PSD-95 interactionsGene therapy : Restore PSD-95 expressionGenetic Associations DLG4 polymorphisms have been linked to:
Schizophrenia
Autism spectrum disorders
Intellectual disability
neurodegenerative disease progression
See Also
External Links
[GeneCards: DLG4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=DLG4)
Synaptic Pathology in Disease DLG4/PSD-95 changes in neurological disorders:
Alzheimer's Disease
Reduced PSD-95 levels in AD hippocampus
Loss of dendritic spines
Impaired synaptic transmission
Correlation with cognitive decline
Parkinson's Disease
Altered striatal PSD-95
Dysregulated NMDA receptor signaling
Excitotoxicity vulnerability
Therapeutic Strategies Targeting PSD-95:
Peptide mimetics : Cell-permeable PSD-95 inhibitorsGene therapy : Viral vector deliverySmall molecules : Stabilizing PSD-95 interactionsAnimal Models
Dlg4 knockout mice : Lethal phenotypesTransgenic models : Overexpression studiesConditional knockouts : Brain-specific deletionAlternative Splicing DLG4 splice variants:
PSD-95 alpha : Full-length isoformPSD-95 beta : Missing N-terminal PDZ domainPSD-95 gamma : Alternative C-terminusDevelopmental regulation : Isoform switchingReferences
[Unknown, Sheng & Hoogenraad, PSD-95 (2007) (2007)](https://doi.org/10.1101/sqb.2007.72.005)
[Feyder et al., PSD-95 and memory (2010) (2010)](https://doi.org/10.1016/j.tins.2010.05.004)
[Liu et al., PSD-95 in AD (2018) (2018)](https://doi.org/10.1016/j.neurobiolaging.2018.01.012) Show full description