| Property | Value |
|---|---|
| Gene Symbol | DLG5 |
| Full Name | Discs Large Homolog 5 |
| Chromosomal Location | 10q22.3 |
| NCBI Gene ID | 9231 |
| OMIM | 604455 |
| Ensembl ID | ENSG00000154655 |
| UniProt | Q9NZU7 |
| Protein Name | Discs large homolog 5 |
| Associated Diseases | Parkinson's Disease, Alzheimer's Disease, Intellectual Disability, Autism, Inflammatory Bowel Disease |
DLG5 (Discs Large Homolog 5) encodes a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins. MAGUK proteins are characterized by their ability to assemble multi-protein signaling complexes at the plasma membrane, organizing proteins into functional units that regulate cell polarity, signal transduction, and synaptic communication[1][2].
DLG5 is a large protein of 1917 amino acids containing multiple functional domains, including PDZ (PSD-95/DLG/ZO-1) domains, an SH3 (Src homology 3) domain, and a GUK (guanylate kinase) domain. These domains enable DLG5 to interact with numerous partner proteins, positioning it at the intersection of multiple signaling pathways critical for neuronal function and survival[3].
In the central nervous system, DLG5 plays essential roles in maintaining neuronal polarity, organizing synaptic structures, and coordinating signaling cascades that regulate synaptic plasticity, learning, and memory. DLG5 has been genetically associated with Parkinson's disease, Alzheimer's disease, and various neurodevelopmental disorders including intellectual disability and autism spectrum disorder[4][5][6].
The human DLG5 gene spans approximately 40 kb on chromosome 10q22.3 and consists of 32 exons. The gene encodes a protein of 1917 amino acids with a molecular weight of approximately 220 kDa.
DLG5 contains several distinct protein-protein interaction domains:
PDZ Domains (1-4):
SH3 Domain:
GUK Domain:
The multi-domain architecture allows DLG5 to serve as a central platform for assembling signaling complexes:
DLG5 was originally identified as a polarity protein[1:1][7]:
Epithelial Cell Polarity:
Neuronal Polarity:
DLG5 is a key component of the postsynaptic density[3:1][8][9]:
Postsynaptic Density (PSD) Scaffold:
Dendritic Spine Formation:
DLG5 plays critical roles in synaptic plasticity mechanisms[10]:
Long-term Potentiation (LTP):
Long-term Depression (LTD):
DLG5 interfaces with multiple signaling cascades[11][12]:
Wnt/β-catenin Signaling:
Hippo Signaling:
Notch Signaling:
DLG5 contributes to neuronal shape and connectivity[13]:
DLG5 is associated with PD risk through multiple mechanisms[4:1][14]:
Genetic Associations:
Disease Mechanisms:
Dopaminergic Neuron Function
Synaptic Dysfunction
Cellular Pathways
In Alzheimer's disease, DLG5 contributes through:
Synaptic Pathology:
Signal Integration:
Evidence:
DLG5 mutations are linked to developmental disorders[5:1][6:1]:
Intellectual Disability:
Autism Spectrum Disorder:
Mechanisms:
| Tissue | Expression Level | Notes |
|---|---|---|
| Brain | Very high | Cortex, hippocampus |
| Heart | High | Cardiomyocytes |
| Kidney | High | Tubular epithelial cells |
| Lung | Moderate | Alveolar epithelium |
| Intestine | Moderate | Epithelial cells |
In the central nervous system:
| Partner | Interaction Domain | Functional Consequence |
|---|---|---|
| PSD-95 | PDZ domains | Synaptic scaffolding |
| NMDA receptors | PDZ domains | Synaptic signaling |
| AMPA receptors | PDZ domains | Synaptic transmission |
| mGluRs | PDZ domains | Plasticity modulation |
| Actin | SH3 domain | Cytoskeletal linkage |
Modulating DLG5 function offers therapeutic opportunities:
Small Molecule Approaches:
Gene Therapy:
| Model | Type | Phenotype |
|---|---|---|
| Dlg5 knockout | Complete | Embryonic lethal (some backgrounds) |
| Dlg5 conditional knockout | Neuron-specific | Synaptic deficits, memory impairment |
| Dlg5 knock-in | Point mutations | Model neurodevelopmental disorders |
Nakamura Y, et al. DLG5 in cell polarity and tissue organization. Nature Cell Biology. 2002. ↩︎ ↩︎
Carreno G, et al. MAGUK proteins and synaptic scaffolding. Current Opinion in Neurobiology. 2012. ↩︎
Siddiqui N, et al. DLG5 in neuronal development and synaptic function. Journal of Neuroscience. 2013. ↩︎ ↩︎
Friedman LM, et al. DLG5 variants and susceptibility to Parkinson's disease. Movement Disorders. 2009. ↩︎ ↩︎
Yoshikawa F, et al. DLG5 mutations and neurodevelopmental disorders. Human Molecular Genetics. 2017. ↩︎ ↩︎
Riviere JB, et al. DLG5 variants in autism spectrum disorder. Molecular Autism. 2012. ↩︎ ↩︎
Lin JY, et al. DLG5 in inflammatory bowel disease and tissue homeostasis. Gastroenterology. 2015. ↩︎
Stalla E, et al. DLG5 in dendritic spine formation and morphology. Cerebral Cortex. 2016. ↩︎
Hu T, et al. DLG5 and postsynaptic density organization. Neuroscience. 2016. ↩︎
Chen X, et al. DLG5 in synaptic plasticity and memory. Learning & Memory. 2020. ↩︎
Zhao J, et al. DLG5 and Wnt signaling in brain development. Developmental Biology. 2019. ↩︎
Iizuka M, et al. DLG5 and hippo signaling pathway. Journal of Cell Science. 2017. ↩︎
Wang H, et al. DLG5 in neuronal polarity and axon guidance. Development. 2018. ↩︎
Park J, et al. DLG5 expression in dopaminergic neurons and PD. Molecular Neurodegeneration. 2019. ↩︎