DLG1 — Discs Large Homolog 1

DLG1 — Discs Large Homolog 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">DLG1 — Discs Large Homolog 1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>DLG1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Discs Large Homolog 1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>3q29</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>1739</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>601014</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000075711</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q12959</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Drug/Approach</td>
</tr>
<tr>
<td class="label">Small molecule</td>
<td>PSD-95/DLG1 disruptors</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-DLG1</td>
</tr>
<tr>
<td class="label">Peptide</td>
<td>NMDA receptor modulators</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Introduction

Dlg1 — Discs Large Homolog 1 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

...

DLG1 — Discs Large Homolog 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">DLG1 — Discs Large Homolog 1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>DLG1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Discs Large Homolog 1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>3q29</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>1739</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>601014</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000075711</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q12959</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Drug/Approach</td>
</tr>
<tr>
<td class="label">Small molecule</td>
<td>PSD-95/DLG1 disruptors</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-DLG1</td>
</tr>
<tr>
<td class="label">Peptide</td>
<td>NMDA receptor modulators</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Introduction

Dlg1 — Discs Large Homolog 1 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

DLG1 (Discs Large Homolog 1) encodes a scaffold protein critical for synaptic organization, cell polarity, and signaling. DLG1 is a member of the membrane-associated guanylate kinase (MAGUK) family and plays essential roles in forming and maintaining excitatory synapses. [@ref2015]

Gene Information

Normal Function

DLG1/MAGUK scaffold protein functions in:

• Synaptic organization: Forms core of postsynaptic density
• [NMDA](/entities/nmda-receptor) receptor anchoring: Recruits NMDA and AMPA receptors to synapses
• Synaptic plasticity: Essential for [LTP](/mechanisms/long-term-potentiation) and LTD
• Cell polarity: Establishes epithelial cell polarity
• Signal transduction: Scaffold for multiple signaling pathways

Disease Associations

Alzheimer's Disease

• Role: Synaptic loss and dysfunction
• Mechanism: DLG1 levels reduced in AD brain; interacts with [amyloid-beta](/proteins/amyloid-beta)
• Research: DLG1 dysfunction contributes to synaptic failure

Parkinson's Disease

• Role: Impaired synaptic function in dopaminergic [neurons](/entities/neurons)
• Mechanism: May affect dopamine receptor signaling

Autism Spectrum Disorder

• Role: Synaptic dysfunction
• Mechanism: DLG1 mutations associated with ASD
• Inheritance: Autosomal dominant

Cancer

• Role: Cell polarity and proliferation
• Mechanism: Tumor suppressor function

Expression Pattern

Ubiquitously expressed with high levels in:

• Brain ([cortex](/brain-regions/cortex), hippocampus)
• Epithelial tissues
• Heart
• Lung

Therapeutic Targeting

Expression Pattern

The DLG1 gene is expressed ubiquitously throughout the brain with particularly high levels in the cerebral cortex, [hippocampus](/brain-regions/hippocampus), and cerebellum. Within the central nervous system, DLG1 is predominantly expressed in excitatory glutamatergic neurons, particularly in pyramidal neurons of layers 2/3 and 5 of the cerebral cortex. The protein localizes to postsynaptic densities of [dendritic spines](/cell-types/dendritic-spines), where it serves as a core scaffold organizing glutamate receptors and associated signaling molecules. Expression increases during postnatal development, reaching adult levels around 3-4 weeks in mice, corresponding to the period of intense synaptogenesis. In human brain tissue, DLG1 mRNA and protein are detected in all cortical layers, with strongest expression in the [entorhinal cortex](/brain-regions/entorhinal-cortex) and hippocampal CA1 region — areas highly vulnerable in [Alzheimer's disease](/diseases/alzheimers-disease).

Molecular Mechanisms

The DLG1 gene encodes a 922-amino acid scaffold protein that contains multiple protein-interaction domains:

• L27 domain (N-terminus): Mediates homodimerization and heterodimerization with other MAGUK proteins
• PDZ domains (PDZ1-3): Bind to C-terminal PDZ-binding motifs on receptors (NMDA NR2 subunits, AMPA receptor stargazin), channels (Kv1.x), and other scaffold proteins
• SH3 domain: Interacts with proline-rich motifs in signaling proteins including RAF kinases and p140Cap
• GUK domain: Guanylate kinase homology domain, catalytically inactive but provides additional protein-protein interaction surfaces

DLG1 functions as a master organizer at excitatory synapses by simultaneously binding multiple synaptic proteins. It interacts with PSD-95 (DLG4), GKAP, Shank, and Homer to form the core postsynaptic density scaffold. Activity-dependent modifications include phosphorylation by several kinases including Src, which enhances synaptic targeting. In disease states, DLG1 interactions with [amyloid-beta](/proteins/amyloid-beta) and [tau](/proteins/tau) contribute to synaptic dysfunction.

Research Directions

Current research on DLG1 includes:

• Understanding how Aβ oligomers disrupt DLG1 synaptic targeting
• Post-mortem studies of DLG1 expression in AD prefrontal cortex
• Developing peptide stabilizers that preserve DLG1 interactions
• Investigating DLG1 phosphorylation patterns in disease vs. healthy brain
• AAV-mediated DLG1 overexpression in mouse models of synaptic dysfunction

Background

The study of Dlg1 — Discs Large Homolog 1 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.

Key Publications

See Also

-- Synaptic Dysfunction

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Autism Spectrum Disorders](/diseases/autism-spectrum-disorders)
• [NMDA Receptor](/entities/nmda-receptor)

External Links

• [NCBI Gene: DLG1](https://www.ncbi.n- [UniProt: DLG1](https://www.uniprot.org/uniprot/Q12959)
• [HGNC: DLG1](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:2901)

References