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Human Endogenous Retrovirus Type W Envelope from Multiple Sclerosis Demyelinating Lesions Shows Unique Solubility and
Benjamin Charvet1,2,3, Justine Pierquin4, Joanna Brunel4,5,6
1GeNeuro Innovation, Lyon, 69008, France. bc@geneuro.com.
Abstract:
In multiple sclerosis (MS), human endogenous retrovirus W family (HERV-W) envelope protein, pHERV-W ENV, limits remyelination and induces microglia-mediated neurodegeneration. To better understand its role, we examined the soluble pHERV-W antigen from MS brain lesions detected by specific antibodies. Physico-chemical and antigenic characteristics confirmed differences between pHERV-W ENV and syncytin-1. pHERV-W ENV monomers and trimers remained associated with membranes, while hexamers self-assembled from monomers into a soluble macrostructure involving sulfatides in MS brain. Extracellular hexamers are stabilized by internal hydrophobic bonds and external hydrophilic moieties. HERV-W studies in MS also suggest that this diffusible antigen may correspond to a previously described high-molecular-weight neurotoxic factor secreted by MS B-cells and thus represents a major agonist in MS pathogenesis. Adapted methods are now needed to identify encoding HERV provirus(es) in affected cells DNA. The properties and origin of MS brain pHERV-W ENV soluble antigen will allow a better understanding of the role of HERVs in MS pathogenesis. The present results anyhow pave the way to an accurate detection of the different forms of pHERV-W ENV antigen with appropriate conditions that remained unseen until now.
Insights
The human endogenous retrovirus W family (HERV-W) envelope protein in multiple sclerosis (MS) forms soluble hexamers in the brain. These structures may drive MS pathogenesis by interacting with microglia.
Area of Science:
- Neuroimmunology
- Virology
- Molecular Biology
Background:
- Multiple sclerosis (MS) involves neurodegeneration and impaired remyelination.
- The human endogenous retrovirus W family (HERV-W) envelope protein (pHERV-W ENV) is implicated in MS pathogenesis.
- pHERV-W ENV is known to limit remyelination and induce microglia-mediated neurodegeneration.
Purpose of the Study:
- To characterize the soluble form of pHERV-W ENV found in MS brain lesions.
- To differentiate pHERV-W ENV from syncytin-1.
- To understand the structural properties and potential role of soluble pHERV-W ENV in MS.
Main Methods:
- Detection of soluble pHERV-W antigen in MS brain lesions using specific antibodies.
- Physico-chemical and antigenic characterization of pHERV-W ENV.
- Analysis of pHERV-W ENV monomer, trimer, and hexamer structures and their association with membranes and sulfatides.
Main Results:
- Physico-chemical analysis confirmed distinct properties of pHERV-W ENV compared to syncytin-1.
- pHERV-W ENV monomers and trimers were membrane-associated, while hexamers self-assembled into soluble macrostructures involving sulfatides in MS brains.
- Extracellular hexamers are stabilized by both internal hydrophobic and external hydrophilic interactions.
Conclusions:
- Soluble pHERV-W ENV hexamers in MS brains may represent a previously identified high-molecular-weight neurotoxic factor secreted by B-cells.
- These findings suggest pHERV-W ENV acts as a key agonist in MS pathogenesis.
- Further research is needed to identify the encoding HERV provirus and develop methods for accurate detection of pHERV-W ENV forms.
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