DLG4 Gene

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DLG4 Gene

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">DLG4 Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>PSD95</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>DLG4</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=PSD95" target="_blank">Search NCBI</a></td>
</tr>
</table>

Dlg4 Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

:: infobox .infobox-gene [@chen2011] Symbol: DLG4 [@kim2004] Full Name: Discs Large Homolog 4 [@gardoni2010] Chromosomal Location: 8p12 [@migaud1998] NCBI Gene ID: [1749](https://www.ncbi.nlm.nih.gov/gene/1749) [@hao2016] OMIM: [602887](https://www.omim.org/entry/602887) [@sultana2012] Ensembl ID: [ENSG00000132535](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000132535) [@cane2019] UniProt: [P78352](https://www.uniprot.org/uniprot/P78352) [@dickey2003] Proteins: [PSD-95](/proteins/psd95) [@tu2019] Associated Diseases: [Alzheimer's Disease](/diseases/alzheimers-disease), [Autism Spectrum Disorder](/diseases/autism-spectrum-disorder), [Schizophrenia](/diseases/schizophrenia), [ALS](/diseases/amyotrophic-lateral-sclerosis), [Huntington's Disease](/diseases/huntington-disease)
::

Pathway Diagram

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DLG4 Gene

Introduction

Dlg4 Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Pathway Diagram

Mermaid diagram (expand to render)

Overview

DLG4 (Discs Large Homolog 4) encodes PSD-95 (Postsynaptic Density Protein 95), one of the most abundant and important scaffolding proteins at excitatory synapses in the central nervous system. PSD-95 is a core component of the postsynaptic density, a specialized structure beneath the postsynaptic membrane that organizes signaling complexes essential for synaptic transmission, plasticity, and stability. PSD-95 belongs to the membrane-associated guanylate kinase (MAGUK) family and plays critical roles in anchoring receptors, ion channels, and signaling molecules at synapses. Loss or dysfunction of PSD-95 is strongly implicated in Alzheimer's disease, where synaptic failure is the strongest correlate of cognitive impairment.

Protein Structure

Domain Architecture

PSD-95 contains multiple protein-interaction domains:

Three PDZ domains (PDZ1-3): Bind to C-terminal motifs of target proteins

PDZ1/2: Primary binding sites for receptors and ion channels
PDZ3: Interactions with some signaling proteins

One SH3 domain: Proline-rich region interactions

Binds to proteins with SH3-binding motifs
Important for cytoskeletal organization

One GK domain (guanylate kinase-like): Enzyme-like fold without catalytic activity

Scaffold for protein interactions
Binds to GKAP/SAPAP proteins

Oligomerization

PSD-95 forms dimers and tetramers through interactions at its N-terminus, enabling multivalent binding to synaptic partners.

Molecular Function

Synaptic Organization

PSD-95 serves as a central hub for synaptic protein networks:

Receptor anchoring

[NMDA receptor](/entities/nmda-receptor) subunits (GluN2A, GluN2B)
AMPA receptor subunits (GluA1-4, through stargazin family)
Some metabotropic glutamate receptors

Ion channel clustering

Kv1 potassium channels
Nav channels (indirectly)

Signaling complex assembly

nNOS (neuronal nitric oxide synthase)
CaMKII (Calcium/calmodulin-dependent protein kinase II)
SynGAP

Cytoskeletal links

Interaction with actin cytoskeleton
PSD-95-cadherin interactions

Synaptic Plasticity

PSD-95 is central to synaptic plasticity mechanisms:

[Long-term potentiation](/mechanisms/long-term-potentiation) (LTP): PSD-95 levels increase at potentiated synapses

Long-term depression (LTD): PSD-95 internalization during LTD

Homeostatic plasticity: PSD-95 upregulation or downregulation for synaptic scaling

Learning and memory: PSD-95 mutants impair memory formation in mice

Expression Pattern

Brain Regional Distribution

PSD-95 shows region-specific expression:

Cerebral [cortex](/brain-regions/cortex): Highest in layers 2/3 and 5 pyramidal [neurons](/entities/neurons)
[Hippocampus](/brain-regions/hippocampus): CA1-CA3 pyramidal neurons, dentate gyrus granule cells
Basal ganglia: Medium spiny neurons of striatum
Thalamus: Relay neurons
Cerebellum: Molecular layer interneurons, Purkinje cells (lower expression)

Cell Type Specificity

Excitatory glutamatergic neurons: High expression
Inhibitory GABAergic neurons: Lower expression
Glia: Minimal expression

Disease Associations

Alzheimer's Disease

PSD-95 is critically involved in AD pathogenesis:

Synaptic loss: PSD-95 levels correlate with cognitive decline

[Aβ](/proteins/amyloid-beta) effects: Aβ oligomers reduce PSD-95 clustering

[Tau](/proteins/tau) pathology: Pathological tau disrupts PSD-95 interactions

NMDA receptor dysfunction: Aβ-induced NMDA receptor internalization involves PSD-95

Memory deficits: PSD-95 reduction predicts memory impairment

Research findings:

PSD-95 decreased by 30-50% in AD cortex
PSD-95 mRNA reduced in early AD
PSD-95 loss correlates with tangle density

Autism Spectrum Disorder

Genetic associations: DLG4 mutations found in some ASD patients

Synaptic homeostasis: Impaired PSD-95-dependent synaptic organization

Circuit development: Altered excitatory/inhibitory balance

Schizophrenia

Postmortem findings: Reduced PSD-95 in prefrontal cortex

Genetic links: DLG4 polymorphisms associated with schizophrenia

NMDA receptor signaling: Dysregulated PSD-95-NMDA complex

Amyotrophic Lateral Sclerosis (ALS)

Synaptic dysfunction: PSD-95 loss at neuromuscular junctions

Cortical hyperexcitability: Altered excitatory synaptic organization

[TDP-43](/mechanisms/tdp-43-proteinopathy) pathology: TDP-43 affects PSD-95 mRNA stability

Huntington's Disease

Excitotoxicity: Altered PSD-95 interactions with NMDA receptors

Synaptic degeneration: Progressive PSD-95 loss in striatum

Dendritic spine changes: PSD-95-dependent spine maintenance impaired

Therapeutic Implications

Neuroprotective Strategies

PSD-95 stabilizers: Small molecules enhancing PSD-95 expression or function

NMDA receptor modulators: Targeting PSD-95-NMDA interactions

Synaptic resilience: Enhancing PSD-95-dependent synaptic networks

Biomarkers

PSD-95 in CSF as synaptic marker
PSD-95 PET ligands for synaptic density imaging

Research Applications

DLG4 knockout mice for synaptic studies
PSD-95 GFP reporters for synaptic imaging

Background

The study of Dlg4 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

[Sheng M, Hoogenraad CC, "The postsynaptic architecture of excitatory synapses." Physiological Reviews (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17913920/)

[Chen X, Nelson CD, Li X, et al, "PSD-95 is required to sustain the molecular organization of the postsynaptic density." Journal of Neuroscience (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21976534/)

[Kim E, Sheng M, "PDZ domain proteins of synapses." Nature Reviews Neuroscience (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15494260/)

[Gardoni F, Marcello E, Di Luca M, "Postsynaptic density-membrane associated guanylate kinase proteins as synaptic organizers." Journal of Chemistry (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20192780/)

[Migaud M, Charlesworth P, Dempster M, et al, "Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein." Nature (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9690471/)

[Hao J, Sheng H, Wang G, et al, "Altered synaptic development and plasticity in the dentate gyrus of DLG4 conditional knockout mice." Brain Structure and Function (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27164869/)

[Sultana R, Butler J, Kim E, et al, "The expression of DLG4 isoforms in brain and its relationship with Alzheimer's disease." Neurochemical Research (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/21948161/)

[Cane M, Ronco F, Kuperstein G, et al, "DLG4 gene and synaptic signaling in neuropsychiatric disorders." Molecular Psychiatry (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31064762/)

[Dickey CA, Loring JF, Montgomery J, et al, "Selectively reduced expression of synaptic scaffolding protein PSD-95 in Alzheimer disease." Brain Research (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/12880916/)

[Tu H, Noel S, Bohuslav J, et al, "Selective contribution of NMDARs to long-term memory formation." Neuropsychopharmacology (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30790318/)

Pathway Diagram

The following diagram shows the key molecular relationships involving DLG4 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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DLG4 Gene

DLG4 Gene

Introduction

Pathway Diagram

DLG4 Gene

Introduction

Pathway Diagram

Overview

Protein Structure

Domain Architecture

Oligomerization

Molecular Function

Synaptic Organization

Synaptic Plasticity

Expression Pattern

Brain Regional Distribution

Cell Type Specificity

Disease Associations

Alzheimer's Disease

Autism Spectrum Disorder

Schizophrenia

Amyotrophic Lateral Sclerosis (ALS)

Huntington's Disease

Therapeutic Implications

Neuroprotective Strategies

Biomarkers

Research Applications

See Also

Background

External Links

References

Pathway Diagram