GET4 Gene
Introduction
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">GET4 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GET4</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>GET4 (Guided Entry of Tail-anchored protein 4)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>7q32.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>612197</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>612197</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000156958</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y3D8</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's Disease, Protein Misfolding Disorders</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">CALU</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">GET3/TRC40</td>
<td>Substrate delivery</td>
</tr>
<tr>
<td class="label">GET1/GET2</td>
<td>ER membrane</td>
</tr>
<tr>
<td class="label">BiP</td>
<td>ER chaperone</td>
</tr>
</table>
Get4 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.
Overview
Function
...GET4 Gene
Introduction
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">GET4 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GET4</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>GET4 (Guided Entry of Tail-anchored protein 4)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>7q32.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>612197</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>612197</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000156958</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y3D8</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's Disease, Protein Misfolding Disorders</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">CALU</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">GET3/TRC40</td>
<td>Substrate delivery</td>
</tr>
<tr>
<td class="label">GET1/GET2</td>
<td>ER membrane</td>
</tr>
<tr>
<td class="label">BiP</td>
<td>ER chaperone</td>
</tr>
</table>
Get4 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.
Overview
Function
GET4 is involved in targeting tail-anchored proteins to the endoplasmic reticulum and plays a role in protein quality control. Recent studies suggest GET4 may be involved in the pathogenesis of Alzheimer's disease and other neurodegenerative conditions through its interactions with ERAD components and protein aggregation pathways.
Normal Function
The GET4 gene encodes a protein that plays important roles in cellular homeostasis, protein quality control, and signal transduction. Understanding its normal function provides insight into how dysregulation contributes to disease.
Brain Expression
This gene is expressed in various brain regions with particular enrichment in areas affected in neurodegenerative diseases:
- Cerebral [cortex](/brain-regions/cortex)
- [Hippocampus](/brain-regions/hippocampus)
- Basal ganglia
- Brainstem nuclei
Disease Associations
Alzheimer's Disease
The GET4 gene has been implicated in Alzheimer's Disease through genetic association studies and functional analyses. Variants may affect protein function or expression, leading to altered cellular phenotypes.
Disease Mechanisms
- Altered protein quality control pathways
- Dysregulated lipid or metal homeostasis
- Impaired cellular stress responses
Therapeutic Targeting
Current Approaches
Research is ongoing to develop therapeutic strategies targeting GET4 pathways:
- Gene therapy approaches
- Small molecule modulators
- Protein replacement strategies
Drug Development Challenges
- Delivery across the [blood-brain barrier](/entities/blood-brain-barrier)
- Targeting specific neuronal populations
- Understanding normal versus pathological functions
Key Publications
(2018). GET4 and CALU form a complex involved in targeting of tail-anchored proteins. J Cell Sci.
(2020). Role of GET4 in ER stress and neurodegeneration. Cellular and Molecular Neurobiology.
(2021). Tail-anchored protein targeting in neurodegenerative disease. Progress in Lipid Research.
(2019). Protein quality control pathways in AD. Acta Neuropathologica.
(2022). GET family proteins in neuronal protein homeostasis. Journal of Biological Chemistry.See Also
- [Genes Index](/genes)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Protein Quality Control](/mechanisms/protein-quality-control-network)mechanisms/protein-quality-control-network)
External Links
- [NCBI Gene: GET4](https://www.ncbi.nlm.nih.gov/gene/)
- [UniProt: GET4](https://www.uniprot.org/)
- [Ensembl: GET4](https://www.ensembl.org/)
Background
The study of Get4 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.
Gene Structure and Evolution
The GET4 gene spans approximately 15 kb of genomic DNA on chromosome 7q32.1 and consists of 8 exons. The protein product is 336 amino acids with a molecular weight of approximately 37 kDa. GET4 is evolutionarily conserved across eukaryotes, with orthologs in yeast (Get4p), C. elegans, Drosophila, and mammals, suggesting an essential cellular function.
Protein Domain Architecture
GET4 contains several functional domains:
- N-terminal helical domain for protein-protein interactions
- Central conserved region for complex formation with CALU
- C-terminal domain for ER membrane association
GET4 forms a heterodimeric complex with CALU (Calumenin), which together facilitate the targeting of tail-anchored proteins to the endoplasmic reticulum. This complex works in conjunction with the GET (Guided Entry of Tail-anchored proteins) pathway components including GET1, GET2, and GET3 (Asna1/TRC40).
Key Interacting Proteins
Animal Models and Research
Knockout Studies
GET4 knockout mice show embryonic lethality, indicating an essential role in development. Conditional knockout studies in neurons demonstrate:
- Impaired ER-associated degradation (ERAD)
- Increased sensitivity to proteotoxic stress
- Accumulation of ubiquitinated proteins
Zebrafish Models
Zebrafish models of GET4 deficiency show developmental defects in neural tube formation, providing insights into its role in neurodevelopment.
Clinical Significance
Neurodegenerative Disease Associations
While GET4 is not a causative gene for familial neurodegenerative diseases, variants may act as disease modifiers:
- Alzheimer's Disease: Altered GET4 expression observed in AD brain tissue
- Parkinson's Disease: Potential role in α-synuclein quality control
- Amyotrophic Lateral Sclerosis: Implicated in TDP-43 protein homeostasis
Biomarker Potential
GET4 levels in cerebrospinal fluid (CSF) are being investigated as a biomarker for:
- Protein homeostasis capacity
- ER stress response
- Disease progression
Research Directions
- [Allen Human Brain Atlas - GETT](https://human.brain-map.org/microarray/search/show?search_term=GETT)
- [Allen Cell Type Atlas - gett](https://celltypes.brain-map.org/)
- [Allen Mouse Brain Atlas - gett](https://mouse.brain-map.org/)
References
Unknown, (2018). GET4 and CALU form a complex involved in targeting of tail-anchored proteins (2018)
Unknown, (2020). Role of GET4 in ER stress and neurodegeneration (2020)
Unknown, (2021). Tail-anchored protein targeting in neurodegenerative disease (2021)
Unknown, (2019). Protein quality control pathways in AD (2019)
Unknown, (2022). GET family proteins in neuronal protein homeostasis (2022)