RELA (p65) Protein

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RELA (p65) Protein

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RELA (p65) Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">RELA (p65) Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>RELA</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>RELA (p65)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=RELA" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/breast-cancer" style="color:#ef9a9a">Breast Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">439 edges</a></td>
</tr>
</table>

RELA (also known as p65) is the key transcriptional activator subunit of the Nuclear Factor kappa-B (NF-κB) transcription factor complex. It plays a critical role in regulating inflammatory, immune, and cell survival responses in the central nervous system. In the context of neurodegenerative diseases, RELA-mediated [NF-κB](/entities/nf-kb) signaling is a major driver of neuroinflammation, a hallmark pathological feature of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). [@mattson2006]

...

RELA (p65) Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">RELA (p65) Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>RELA</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>RELA (p65)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=RELA" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/breast-cancer" style="color:#ef9a9a">Breast Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">439 edges</a></td>
</tr>
</table>

RELA (also known as p65) is the key transcriptional activator subunit of the Nuclear Factor kappa-B (NF-κB) transcription factor complex. It plays a critical role in regulating inflammatory, immune, and cell survival responses in the central nervous system. In the context of neurodegenerative diseases, RELA-mediated [NF-κB](/entities/nf-kb) signaling is a major driver of neuroinflammation, a hallmark pathological feature of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). [@mattson2006]

[@kaltschmidt2009]

Overview

The RELA gene (also known as NFKB3) encodes the p65 subunit, which is the principal transactivating component of the NF-κB heterodimer p65/p50. This protein is a member of the Rel homology domain (RHD) family and is essential for nearly all NF-κB-dependent gene transcription. In the brain, RELA is expressed in [neurons](/entities/neurons), [astrocytes](/entities/astrocytes), [microglia](/cell-types/microglia-neuroinflammation), and oligodendrocytes, where it responds to various pathological stimuli including [amyloid-beta](/proteins/amyloid-beta) plaques, [alpha-synuclein](/proteins/alpha-synuclein) aggregates, and mitochondrial dysfunction. [@chen2012]

Structure

The RELA protein contains several distinct structural domains: [@sivandzade2019]

Rel Homology Domain (RHD): The N-terminal ~300 amino acids comprise the RHD, which mediates DNA binding, dimerization, and interaction with IκB inhibitors
Transactivation Domain (TAD): The C-terminal region contains two TADs (TAD1 and TAD2) that recruit transcriptional coactivators including CBP/p300
RHD: Enables dimerization with p50, p52, c-Rel, or RELB to form functional NF-κB dimers

The three-dimensional structure reveals that RELA forms a butterfly-shaped dimer that clamps around DNA at κB enhancer sites, with each monomer contributing to transcription activation through protein-protein interactions with the basal transcription machinery. [@ghosh2008]

Normal Function

NF-κB Signaling Pathway

The canonical NF-κB pathway is activated by proinflammatory cytokines (TNF-α, IL-1β), pathogen-associated molecular patterns (LPS), and cellular stress. In the resting state, NF-κB dimers are sequestered in the cytoplasm by IκBα and other IκB proteins. Upon stimulation: [@oneill2007]

IκB Kinase (IKK) activation: IKKβ phosphorylates IκBα at Ser32/36

Ubiquitination and degradation: Polyubiquitinated IκBα is degraded by the 26S proteasome

Nuclear translocation: Free p65/p50 dimer translocates to the nucleus

Gene transcription: RELA recruits coactivators and initiates transcription of target genes

Key Target Genes

RELA regulates hundreds of genes involved in:

Inflammatory mediators: TNF-α, IL-1β, IL-6, COX-2, iNOS
Anti-apoptotic proteins: Bcl-2, Bcl-xL, c-IAP1/2, XIAP
Acute phase proteins: CRP, serum amyloid A
Cell adhesion molecules: ICAM-1, VCAM-1, E-selectin

Role in Neurodegenerative Diseases

Alzheimer's Disease

In Alzheimer's disease, RELA activation occurs through multiple pathways:

Amyloid-beta (Aβ) stimulation: Aβ oligomers and fibrils activate NF-κB in neurons and microglia through engagement of pattern recognition receptors including TLRs and [RAGE](/entities/rage-receptor)
[Tau](/proteins/tau)-mediated activation: Hyperphosphorylated tau can activate NF-κB signaling, creating a vicious cycle of inflammation and pathology
Microglial activation: Chronic RELA activation drives microglial production of proinflammatory cytokines that contribute to synaptic loss and neuronal death

The presence of activated RELA in the nuclei of neurons and glia near amyloid plaques suggests a direct role in AD pathogenesis. Studies have shown that Aβ-induced neurotoxicity is partially mediated through NF-κB-dependent gene expression.

Parkinson's Disease

In Parkinson's disease:

Dopaminergic neuron vulnerability: RELA activation in the substantia nigra pars compacta contributes to inflammation-mediated dopaminergic neuron death
Microglial activation: Chronic activation of microglial RELA by α-synuclein aggregates maintains a proinflammatory environment
Mitochondrial dysfunction: NF-κB responds to mitochondrial [ROS](/entities/reactive-oxygen-species) and can either promote survival or cell death depending on context

Amyotrophic Lateral Sclerosis

In ALS:

Motor neuron degeneration: RELA activation in motor neurons and surrounding glial cells promotes inflammatory cytokine production
Protein aggregation: NF-κB activation may be triggered by misfolded SOD1, [TDP-43](/mechanisms/tdp-43-proteinopathy), and FUS aggregates
Glial cell involvement: Astrocytic and microglial NF-κB contributes to non-cell autonomous motor neuron death

Other Neurodegenerative Disorders

Multiple Sclerosis (MS): RELA-mediated inflammation contributes to demyelination and axonal loss
Huntington's Disease: NF-κB activation occurs in response to mutant [huntingtin protein](/proteins/huntingtin)
Frontotemporal Dementia: Inflammatory pathways involving RELA are dysregulated

Therapeutic Implications

NF-κB Inhibitors in Development

Several therapeutic strategies targeting RELA/NF-κB are being explored:

Small molecule inhibitors: Compounds that block IKK activity, RELA DNA binding, or protein-protein interactions
Natural compounds: Curcumin, resveratrol, and epigallocatechin-3-gallate (EGCG) have NF-κB inhibitory properties
Gene therapy approaches: Dominant-negative IκB expression to block NF-κB activation

Challenges

The pleiotropic nature of NF-κB signaling makes targeted therapy challenging, as complete inhibition could impair normal immune function and cell survival mechanisms. Selective modulation in specific cell types (e.g., microglia) remains an important research goal.

Background

The study of Rela (P65) Protein 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: P06579 (RELA Human)](https://www.uniprot.org/uniprot/P06579)
[PDB: 1RAM (NF-κB p50/p65 Heterodimer)](https://www.rcsb.org/structure/1RAM)
[GeneCards: RELA Gene](https://www.genecards.org/cgi-bin/carddisp.pl?gene=RELA)

References

[Unknown, Mattson, M.P. & Meffert, M.K. (2006). Roles for NF-κB in nerve cell survival, plasticity, and disease. Cell Death & Differentiation, 13(5), 852-860 (2006)](https://pubmed.ncbi.nlm.nih.gov/16410796/)

[Unknown, Kaltschmidt, B. & Kaltschmidt, C. (2009). NF-κB in the nervous system. Cold Spring Harbor Perspectives in Biology, 1(3), a001271 (2009)](https://pubmed.ncbi.nlm.nih.gov/20066108/)

[Chen, C.H. et al., (2012). NF-κB as a therapeutic target in neurodegenerative diseases. Expert Opinion on Therapeutic Targets, 16(12), 1177-1188 (2012)](https://pubmed.ncbi.nlm.nih.gov/23066856/)

[Sivandzade, F. et al., (2019). NF-κB inhibition in microglia: A potential therapeutic approach for Alzheimer's disease? Pharmacological Research, 147, 104361 (2019)](https://pubmed.ncbi.nlm.nih.gov/31220543/)

[Unknown, Ghosh, S. & Hayden, M.S. (2008). New regulators of NF-κB in inflammation. Nature Reviews Immunology, 8(11), 837-848 (2008)](https://doi.org/10.1038/nri2423)

[Unknown, O'Neill, L.A. & Bowie, A.G. (2007). The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nature Reviews Immunology, 7(5), 353-364 (2007)](https://pubmed.ncbi.nlm.nih.gov/17435743/)

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Related Entities

RELAPROTEIN

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📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

74

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

RELA (p65) Protein

RELA (p65) Protein

Introduction

RELA (p65) Protein

Introduction

Overview

Structure

Normal Function

NF-κB Signaling Pathway

Key Target Genes

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Other Neurodegenerative Disorders

Therapeutic Implications

NF-κB Inhibitors in Development

Challenges

See Also

Background

External Links

References

💬 Discussion