TNFR1 Protein

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TNFR1 Protein

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TNFR1 Protein

Introduction

Tumor Necrosis Factor Receptor 1 (TNFR1, also known as TNFRSF1A) is a member of the tumor necrosis factor receptor superfamily that transduces the pro-inflammatory and pro-apoptotic effects of tumor necrosis factor-alpha (TNF-α). TNFR1 is a master regulator of inflammation, cell survival, and cell death pathways. In the central nervous system, TNFR1 signaling contributes to neuroinflammation, excitotoxicity, and neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and traumatic brain injury. Understanding TNFR1's dual roles in both protective immunity and pathological neurodegeneration is crucial for developing targeted therapeutics.

Protein Infobox

<div class="infobox infobox-protein"> [@mccoy2007]
<div class="infobox-header">TNFR1 Protein</div> [@heneka2015]
<div class="infobox-row"><strong>Gene:</strong> [TNFRSF1A](/genes/tnfrsf1a)</div> [@sriram2075]
<div class="infobox-row"><strong>UniProt ID:</strong> [P19438](https://www.uniprot.org/uniprot/P19438)</div> [@chao2009]
<div class="infobox-row"><strong>PDB Structure:</strong> 1TNR, 1FVC, 2AZ5, 5US7</div> [@chen2007]
<div class="infobox-row"><strong>Molecular Weight:</strong> ~55 kDa (type I transmembrane protein)</div> [@montgomery2011]
<div class="infobox-row"><strong>Subcellular Localization:</strong> Plasma membrane, endosomes, Golgi apparatus</div> [@decourt2007]
<div class="infobox-row"><strong>Protein Family:</strong> TNF receptor superfamily, TNFR1 subfamily</div> [@roh2005]
</div> [@yang2012]

Structure

...

TNFR1 Protein

Introduction

Tumor Necrosis Factor Receptor 1 (TNFR1, also known as TNFRSF1A) is a member of the tumor necrosis factor receptor superfamily that transduces the pro-inflammatory and pro-apoptotic effects of tumor necrosis factor-alpha (TNF-α). TNFR1 is a master regulator of inflammation, cell survival, and cell death pathways. In the central nervous system, TNFR1 signaling contributes to neuroinflammation, excitotoxicity, and neuronal loss in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and traumatic brain injury. Understanding TNFR1's dual roles in both protective immunity and pathological neurodegeneration is crucial for developing targeted therapeutics.

Protein Infobox

<div class="infobox infobox-protein"> [@mccoy2007]
<div class="infobox-header">TNFR1 Protein</div> [@heneka2015]
<div class="infobox-row"><strong>Gene:</strong> [TNFRSF1A](/genes/tnfrsf1a)</div> [@sriram2075]
<div class="infobox-row"><strong>UniProt ID:</strong> [P19438](https://www.uniprot.org/uniprot/P19438)</div> [@chao2009]
<div class="infobox-row"><strong>PDB Structure:</strong> 1TNR, 1FVC, 2AZ5, 5US7</div> [@chen2007]
<div class="infobox-row"><strong>Molecular Weight:</strong> ~55 kDa (type I transmembrane protein)</div> [@montgomery2011]
<div class="infobox-row"><strong>Subcellular Localization:</strong> Plasma membrane, endosomes, Golgi apparatus</div> [@decourt2007]
<div class="infobox-row"><strong>Protein Family:</strong> TNF receptor superfamily, TNFR1 subfamily</div> [@roh2005]
</div> [@yang2012]

Structure

TNFR1 is a type I transmembrane receptor with characteristic features: [@dong2002]

Extracellular domain (ECD): Contains four cysteine-rich domains (CRDs) that bind TNF-α
Transmembrane domain: Single α-helical transmembrane segment
Cytoplasmic domain (DD): Contains the death domain (~70 aa) for signaling
Pre-ligand assembly: TNFR1 forms pre-assembled trimers in the membrane
Soluble receptor: Can be shed as a soluble receptor (sTNFR1) that neutralizes TNF-α

Crystal structures of TNFR1 (PDB: 1TNR, 1FVC) show the trimeric receptor-ligand complex. [@zhang2012]

Normal Function

TNFR1 signaling has complex physiological roles:

Pro-inflammatory signaling: Activates [NF-κB](/entities/nf-kb) and MAPK pathways via [TRADD](/genes/tradd)/TRAF2

[Apoptosis](/entities/apoptosis) induction: Can trigger apoptosis through [FADD](/genes/fadd)/[caspase-8](/entities/caspases) pathway

[Necroptosis](/entities/necroptosis): Partners with [RIPK3](/genes/ripk3) for necroptotic cell death under certain conditions

Immune regulation: Essential for mounting inflammatory responses to infection

Cell survival: NF-κB activation promotes cell survival and proliferation

Role in Neurodegeneration

Alzheimer's Disease

TNFR1 is upregulated in AD brains and contributes to pathogenesis:

Neuroinflammation: [TNF-α](/proteins/tnf-alpha-protein)/TNFR1 signaling drives chronic neuroinflammation in AD
Synaptic dysfunction: TNFR1 activation impairs synaptic plasticity and memory
Amyloid-β synergy: [Aβ](/proteins/amyloid-beta) and TNF-α synergistically promote neuronal death
Glial activation: TNFR1 on [microglia](/cell-types/microglia-neuroinflammation) and [astrocytes](/entities/astrocytes) promotes pro-inflammatory phenotype
Therapeutic targeting: TNF-α inhibitors (etanercept, infliximab) have shown promise in AD models

Parkinson's Disease

TNFR1 contributes to dopaminergic neuron loss:

Mitochondrial dysfunction: [TNF-α](/proteins/tnf-alpha-protein) signaling through TNFR1 impairs mitochondrial function
Microglial activation: TNFR1 mediates microglial activation and neurotoxic cytokine release
[Alpha-synuclein](/proteins/alpha-synuclein): TNF-α potentiates α-synuclein toxicity
Neuroprotection: TNFR1 deficiency protects against MPTP-induced PD

Amyotrophic Lateral Sclerosis

TNFR1 plays a role in motor neuron degeneration:

Astrocyte activation: TNFR1 on astrocytes promotes inflammatory responses
Microglial toxicity: TNFR1-mediated inflammation contributes to non-cell autonomous damage
Disease progression: TNFR1 levels correlate with disease severity

Stroke and Traumatic Brain Injury

TNFR1 mediates secondary neuronal damage:

Ischemic injury: [TNF-α](/proteins/tnf-alpha-protein)/TNFR1 signaling exacerbates ischemic brain damage
Excitotoxicity: TNFR1 synergizes with glutamate toxicity
[Blood-brain barrier](/entities/blood-brain-barrier) disruption: TNFR1 contributes to BBB breakdown

Therapeutic Targeting

TNFR1 is a major drug target for neuroinflammatory disorders:

TNF-α inhibitors: Etanercept (Enbrel), Infliximab (Remicade), Adalimumab (Humira)
TNFR1 antagonists: Soluble receptors and blocking antibodies
Signaling inhibitors: [NF-κB](/entities/nf-kb) and MAPK pathway inhibitors
Challenges: Systemic TNF inhibition causes immunosuppression
Brain-penetrant drugs: Newer approaches aim to target CNS TNFR1 selectively

External Links

[UniProt: P19438](https://www.uniprot.org/uniprot/P19438)
[PDB structures](https://www.rcsb.org/search?q=uniprot:P19438)
[GeneCards: TNFRSF1A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNFRSF1A)

References

[Banner et al., Crystal structure of the soluble human 55 kd TNF receptor (1993)](https://doi.org/10.1016/0092-8674(93)

[Unknown, McCoy MK & Tansey MG, TNF signaling inhibition in the CNS (2007)](https://doi.org/10.1016/j.jneuroim.2007.11.002)

[Heneka MT et al., Neuroinflammation in Alzheimer's disease (2015)](https://doi.org/10.1016/S1474-4422(15)

[Unknown, Sriram K & O'Callaghan JP, Divergent roles of TNF in CNS injury (2075)](https://doi.org/10.1002/j.1460-2075.2006.tb02794.x)

[Chao Y et al., TNF-alpha and neurodegenerative disease (2009)](https://doi.org/10.1016/j.neuropharm.2009.04.025)

[Chen J et al., TNFR1 mediates TNF-α-induced neurotoxicity (2007)](https://pubmed.ncbi.nlm.nih.gov/17308394/)

[Montgomery SL et al., TNF in Alzheimer's disease (2011)](https://pubmed.ncbi.nlm.nih.gov/21620607/)

[Decourt B et al., TNFRSF1A polymorphisms and sporadic Alzheimer's disease (2007)](https://pubmed.ncbi.nlm.nih.gov/17554242/)

[Roh HS et al., Intracerebral injection of TNF-alpha induces motor neuron degeneration (2005)](https://pubmed.ncbi.nlm.nih.gov/15645172/)

[Yang L et al., TNFR1 deficiency protects against MPTP-induced parkinsonism (2012)](https://pubmed.ncbi.nlm.nih.gov/22965132/)

[Dong Y et al., Caspase-8 and FADD in TNF-induced apoptosis (2002)](https://pubmed.ncbi.nlm.nih.gov/11854267/)

[Zhang C et al., RIPK1/RIPK3 mediates TNF-induced necroptosis (2012)](https://pubmed.ncbi.nlm.nih.gov/21832145/)

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Related Entities

TNFR1PROTEIN

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

65%

Debates

0

Incoming

13

Outgoing

14

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

TNFR1 Protein

TNFR1 Protein

Introduction

Protein Infobox

Structure

TNFR1 Protein

Introduction

Protein Infobox

Structure

Normal Function

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Stroke and Traumatic Brain Injury

Therapeutic Targeting

See Also

External Links

References

💬 Discussion