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PHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis.

ABSTRACT: Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

SUBMITTER: Kremer D

PROVIDER: S-EPMC6660731 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis.

Kremer David D Gruchot Joel J Weyers Vivien V Oldemeier Lisa L Göttle Peter P Healy Luke L Ho Jang Jeong J Kang T Xu Yu Y Volsko Christina C Dutta Ranjan R Trapp Bruce D BD Perron Hervé H Hartung Hans-Peter HP Küry Patrick P

Proceedings of the National Academy of Sciences of the United States of America 20190618 30

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its e ...[more]

PMID: 31213545

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Project description:BACKGROUND:Small-diameter, myelinated axons are selectively susceptible to dysfunction in several inflammatory PNS and CNS diseases, resulting in pain and degeneration, but the mechanism is not known. METHODS:We used in vivo confocal microscopy to compare the effects of inflammation in experimental autoimmune neuritis (EAN), a model of Guillain-Barré syndrome (GBS), on mitochondrial function and transport in large- and small-diameter axons. We have compared mitochondrial function and transport in vivo in (i) healthy axons, (ii) axons affected by experimental autoimmune neuritis, and (iii) axons in which mitochondria were focally damaged by laser induced photo-toxicity. RESULTS:Mitochondria affected by inflammation or laser damage became depolarized, fragmented, and immobile. Importantly, the loss of functional mitochondria was accompanied by an increase in the number of mitochondria transported towards, and into, the damaged area, perhaps compensating for loss of ATP and allowing buffering of the likely excessive Ca2+ concentration. In large-diameter axons, healthy mitochondria were found to move into the damaged area bypassing the dysfunctional mitochondria, re-populating the damaged segment of the axon. However, in small-diameter axons, the depolarized mitochondria appeared to "plug" the axon, obstructing, sometimes completely, the incoming (mainly anterograde) transport of mitochondria. Over time (~?2 h), the transported, functional mitochondria accumulated at the obstruction, and the distal part of the small-diameter axons became depleted of functional mitochondria. CONCLUSIONS:The data show that neuroinflammation, in common with photo-toxic damage, induces depolarization and fragmentation of axonal mitochondria, which remain immobile at the site of damage. The damaged, immobile mitochondria can "plug" myelinated, small-diameter axons so that successful mitochondrial transport is prevented, depleting the distal axon of functioning mitochondria. Our observations may explain the selective vulnerability of small-diameter axons to dysfunction and degeneration in a number of neurodegenerative and neuroinflammatory disorders.

Dataset Information

PHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis.

Publications

pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis.

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