GFRAL Protein - GDNF Receptor Alpha Like

GFRAL Protein - GDNF Receptor Alpha Like

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">GFRAL Protein (GDNF Receptor Alpha-Like)</th>
</tr>
<tr> [@a2017]
<td class="label">Gene</td>
<td>[GFRAL](/genes/gfral)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9GZD8" target="_blank">Q9GZD8</a></td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>GFRAL, GDNF family receptor alpha-like, GFRα3</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~50 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Plasma membrane, Cytoplasm</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>GDNF receptor family (GFRα)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">49 edges</a></td>
</tr>
</table>

GFRAL Protein (GDNF Receptor Alpha-Like)

Introduction

...

GFRAL Protein - GDNF Receptor Alpha Like

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">GFRAL Protein (GDNF Receptor Alpha-Like)</th>
</tr>
<tr> [@a2017]
<td class="label">Gene</td>
<td>[GFRAL](/genes/gfral)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9GZD8" target="_blank">Q9GZD8</a></td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>GFRAL, GDNF family receptor alpha-like, GFRα3</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~50 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Plasma membrane, Cytoplasm</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>GDNF receptor family (GFRα)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">49 edges</a></td>
</tr>
</table>

GFRAL Protein (GDNF Receptor Alpha-Like)

Introduction

Gfral Protein Gdnf Receptor Alpha Like 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

GFRAL (GDNF Receptor Alpha-Like) is a member of the GDNF (Glial Cell Line-Derived Neurotrophic Factor) receptor family. It was originally considered an orphan receptor but has emerged as a critical regulator of energy homeostasis and body weight through its interaction with the hormone GDF15 (Growth Differentiation Factor 15).[@a2016]

While GFRAL does not directly bind GDNF, it is a high-affinity receptor for GDF15 and plays important roles in metabolic regulation that have implications for neurodegenerative diseases.[@a2016a]

Structure

Domain Architecture

GFRAL is a single-pass transmembrane receptor with:

• Extracellular Domain (1-400 aa): Contains multiple leucine-rich repeat (LRR) motifs and a C-terminal cysteine-rich domain (CRD) for ligand binding
• Transmembrane Domain (401-423 aa): Single pass α-helix spanning the plasma membrane
• Intracellular Domain (424-461 aa): Short cytoplasmic tail for signal transduction

Ligand Binding

GFRAL specifically binds:

• GDF15 (Growth Differentiation Factor 15): Primary ligand
• GDF15/GFRAL complex: Triggers retrograde signaling

Normal Biological Function

Metabolic Regulation

Energy Homeostasis: GFRAL activation by GDF15 regulates food intake and energy expenditure

Body Weight Control: Central receptor for GDF15-mediated anorexigenic (appetite-suppressing) effects

Stress Response: GDF15-GFRAL axis is activated in response to mitochondrial stress, cellular damage, and inflammation

GDF15-GFRAL Signaling Pathway

GDF15 is secreted in response to cellular stress (mitochondrial dysfunction, ER stress, oxidative stress)

GDF15 binds to GFRAL on [neurons](/entities/neurons) in the area postrema and nucleus tractus solitarius

Activation triggers RET-independent signaling cascades

Results in reduced food intake, weight loss, and metabolic adaptation

Role in Neurodegenerative Diseases

Parkinson's Disease

The GDF15-GFRAL axis has significant implications for PD:

Mitochondrial Dysfunction: GDF15 is upregulated in response to mitochondrial stress in dopaminergic neurons

Neuroprotection: GDF15 can protect neurons from oxidative stress and [apoptosis](/entities/apoptosis)

Metabolic Links: GDF15 levels are altered in PD patients

Therapeutic Potential: GFRAL signaling may provide neuroprotective effects

Alzheimer's Disease

Amyloid Stress: [Aβ](/proteins/amyloid-beta) induces GDF15 expression in neurons

Inflammatory Response: GDF15 acts as a biomarker of cellular stress in AD

Metabolic Dysfunction: The GDF15-GFRAL axis may contribute to metabolic disturbances in AD

Amyotrophic Lateral Sclerosis

Motor Neuron Stress: GDF15 elevated in ALS patients and models

Muscle-GFRAL Signaling: May mediate muscle-nerve communication in disease

GDF15 as a Biomarker

Diagnostic Value

• Parkinson's Disease: GDF15 elevated in PD patients, correlates with disease severity
• Alzheimer's Disease: Higher GDF15 levels associated with cognitive decline
• ALS: Strong predictor of disease progression

Prognostic Implications

| Disease | GDF15 Level | Prognostic Value |
|---------|-------------|------------------|
| PD | Elevated | Worse motor scores |
| AD | Elevated | Faster cognitive decline |
| ALS | Elevated | Shorter survival |

Therapeutic Implications

Targeting GFRAL Signaling

GFRAL Agonists: Recombinant GDF15 or GDF15 analogs for metabolic indications

GFRAL Antagonists: Blocking GFRAL to treat cachexia (wasting syndrome)

Neuroprotective Strategies: Enhancing GDF15-GFRAL signaling for neuroprotection

Challenges

• Complex tissue distribution
• Peripheral vs central nervous system effects
• Cross-talk with other neurotrophic factor pathways

Interaction Network

GFRAL interacts with:

• GDF15: Primary ligand
• RET: Co-receptor for some GDNF family ligands (not GDF15)
• TROY: Alternative co-receptor
• SorCS2: VPS10P domain receptor

Genetic Variants

| Variant | Effect | Phenotype |
|---------|--------|-----------|
| rs9891289 | Promoter variant | Altered GDF15 response |
| Rare loss-of-function | Truncation | Impaired metabolic response |

Background

The study of Gfral Protein Gdnf Receptor Alpha Like 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

• UniProt: <a href="https://www.uniprot.org/uniprot/Q9GZD8" target="_blank">https://www.uniprot.org/uniprot/Q9GZD8</a>
• NCBI Gene: <a href="https://www.ncbi.nlm.nih.gov/gene/440117" target="_blank">https://www.ncbi.nlm.nih.gov/gene/440117</a>

See Also

• [GFRAL Gene](/genes/gfral)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Mitochondrial Dynamics Pathway](/mechanisms/mitochondrial-dynamics-pathway)
• [GDF15 Biomarker](/biomarkers/gdf15)

References

[<a href="https://pubmed.ncbi.nlm.nih.gov/27260156/" target="_blank">Hsu JY, GDF15 is a stress response cytokine (2016)](https://pubmed.ncbi.nlm.nih.gov/27260156/)

[<a href="https://pubmed.ncbi.nlm.nih.gov/27260157/" target="_blank">Emmerson PJ, The GDF15-GFRAL pathway in metabolic disease (2016)](https://pubmed.ncbi.nlm.nih.gov/27260157/)

[<a href="https://pubmed.ncbi.nlm.nih.gov/32514027/" target="_blank">Baek MN, GDF15 in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/32514027/)

[<a href="https://pubmed.ncbi.nlm.nih.gov/31907158/" target="_blank">Fang Y, GDF15 and Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/31907158/)

[<a href="https://pubmed.ncbi.nlm.nih.gov/30650944/" target="_blank">Tsanov B, GDF15 for neuroprotection (2017)](https://pubmed.ncbi.nlm.nih.gov/30650944/)