Limiting neuronal nogo receptor 1 signaling during experimental autoimmune encephalomyelitis preserves axonal transport and abrogates inflammatory demyelination

Jae Young Lee, Min Joung Kim, Speros Thomas, Viola Oorschot, Georg Ramm, Pei Mun Aui, Yuichi Sekine, Devy Deliyanti, Jennifer Wilkinson-Berka, Be’eri Niego, Alan R. Harvey, Paschalis Theotokis, Catriona McLean, Stephen M. Strittmatter, Steven Petratos

Research output: Contribution to journalArticleResearchpeer-review

Abstract

We previously identified that ngr1 allele deletion limits the severity of experimental autoimmune encephalomyelitis (EAE) by preserving axonal integrity. However, whether this favorable outcome observed in EAE is a consequence of an abrogated neuronal-specific pathophysiological mechanism, is yet to be defined. Here we show that, Cre-loxP-mediated neuron-specific deletion of ngr1 preserved axonal integrity, whereas its re-expression in ngr1-/- female mice potentiated EAE-axonopathy. As a corollary, myelin integrity was preserved under Cre deletion in ngr1flx/flx, retinal ganglion cell axons whereas, significant demyelination occurred in the ngr1-/- optic nerves following the re-introduction of NgR1. Moreover, Cre-loxP-mediated axon-specific deletion of ngr1 in ngr1flx/flx mice also demonstrated efficient anterograde transport of fluorescently-labeled ChTxβ in the optic nerves of EAE-induced mice. However, the anterograde transport of ChTxβ displayed accumulation in optic nerve degenerative axons of EAE-induced ngr1-/- mice, when NgR1 was reintroduced but was shown to be transported efficiently in the contralateral non- recombinant adeno-associated virus serotype 2-transduced optic nerves of these mutant mice. We further identified that the interaction between the axonal motor protein, Kinesin-1 and collapsin response mediator protein 2 (CRMP2) was unchanged upon Cre deletion of ngr1. Whereas, this Kinesin-1/CRMP2 association was reduced when NgR1 was re-expressed in the ngr1-/-optic nerves. Our data suggest that NgR1 governs axonal degeneration in the context of inflammatory-mediated demyelination through the phosphorylation of CRMP2 by stalling axonal vesicular transport. Moreover, axon-specific deletion of ngr1 preserves axonal transport mechanisms, blunting the induction of inflammatory demyelination and limiting the severity of EAE.

Original languageEnglish
Pages (from-to)5562-5580
Number of pages19
JournalJournal of Neuroscience
Volume39
Issue number28
DOIs
Publication statusPublished - 10 Jul 2019

Keywords

  • Axonal degeneration
  • Collapsin response mediator protein 2
  • Demyelination
  • Experimental autoimmune encephalomyelitis
  • Kinesin-1
  • Nogo receptor 1

Cite this

Lee, Jae Young ; Kim, Min Joung ; Thomas, Speros ; Oorschot, Viola ; Ramm, Georg ; Aui, Pei Mun ; Sekine, Yuichi ; Deliyanti, Devy ; Wilkinson-Berka, Jennifer ; Niego, Be’eri ; Harvey, Alan R. ; Theotokis, Paschalis ; McLean, Catriona ; Strittmatter, Stephen M. ; Petratos, Steven. / Limiting neuronal nogo receptor 1 signaling during experimental autoimmune encephalomyelitis preserves axonal transport and abrogates inflammatory demyelination. In: Journal of Neuroscience. 2019 ; Vol. 39, No. 28. pp. 5562-5580.
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title = "Limiting neuronal nogo receptor 1 signaling during experimental autoimmune encephalomyelitis preserves axonal transport and abrogates inflammatory demyelination",
abstract = "We previously identified that ngr1 allele deletion limits the severity of experimental autoimmune encephalomyelitis (EAE) by preserving axonal integrity. However, whether this favorable outcome observed in EAE is a consequence of an abrogated neuronal-specific pathophysiological mechanism, is yet to be defined. Here we show that, Cre-loxP-mediated neuron-specific deletion of ngr1 preserved axonal integrity, whereas its re-expression in ngr1-/- female mice potentiated EAE-axonopathy. As a corollary, myelin integrity was preserved under Cre deletion in ngr1flx/flx, retinal ganglion cell axons whereas, significant demyelination occurred in the ngr1-/- optic nerves following the re-introduction of NgR1. Moreover, Cre-loxP-mediated axon-specific deletion of ngr1 in ngr1flx/flx mice also demonstrated efficient anterograde transport of fluorescently-labeled ChTxβ in the optic nerves of EAE-induced mice. However, the anterograde transport of ChTxβ displayed accumulation in optic nerve degenerative axons of EAE-induced ngr1-/- mice, when NgR1 was reintroduced but was shown to be transported efficiently in the contralateral non- recombinant adeno-associated virus serotype 2-transduced optic nerves of these mutant mice. We further identified that the interaction between the axonal motor protein, Kinesin-1 and collapsin response mediator protein 2 (CRMP2) was unchanged upon Cre deletion of ngr1. Whereas, this Kinesin-1/CRMP2 association was reduced when NgR1 was re-expressed in the ngr1-/-optic nerves. Our data suggest that NgR1 governs axonal degeneration in the context of inflammatory-mediated demyelination through the phosphorylation of CRMP2 by stalling axonal vesicular transport. Moreover, axon-specific deletion of ngr1 preserves axonal transport mechanisms, blunting the induction of inflammatory demyelination and limiting the severity of EAE.",
keywords = "Axonal degeneration, Collapsin response mediator protein 2, Demyelination, Experimental autoimmune encephalomyelitis, Kinesin-1, Nogo receptor 1",
author = "Lee, {Jae Young} and Kim, {Min Joung} and Speros Thomas and Viola Oorschot and Georg Ramm and Aui, {Pei Mun} and Yuichi Sekine and Devy Deliyanti and Jennifer Wilkinson-Berka and Be’eri Niego and Harvey, {Alan R.} and Paschalis Theotokis and Catriona McLean and Strittmatter, {Stephen M.} and Steven Petratos",
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Limiting neuronal nogo receptor 1 signaling during experimental autoimmune encephalomyelitis preserves axonal transport and abrogates inflammatory demyelination. / Lee, Jae Young; Kim, Min Joung; Thomas, Speros; Oorschot, Viola; Ramm, Georg; Aui, Pei Mun; Sekine, Yuichi; Deliyanti, Devy; Wilkinson-Berka, Jennifer; Niego, Be’eri; Harvey, Alan R.; Theotokis, Paschalis; McLean, Catriona; Strittmatter, Stephen M.; Petratos, Steven.

In: Journal of Neuroscience, Vol. 39, No. 28, 10.07.2019, p. 5562-5580.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Limiting neuronal nogo receptor 1 signaling during experimental autoimmune encephalomyelitis preserves axonal transport and abrogates inflammatory demyelination

AU - Lee, Jae Young

AU - Kim, Min Joung

AU - Thomas, Speros

AU - Oorschot, Viola

AU - Ramm, Georg

AU - Aui, Pei Mun

AU - Sekine, Yuichi

AU - Deliyanti, Devy

AU - Wilkinson-Berka, Jennifer

AU - Niego, Be’eri

AU - Harvey, Alan R.

AU - Theotokis, Paschalis

AU - McLean, Catriona

AU - Strittmatter, Stephen M.

AU - Petratos, Steven

PY - 2019/7/10

Y1 - 2019/7/10

N2 - We previously identified that ngr1 allele deletion limits the severity of experimental autoimmune encephalomyelitis (EAE) by preserving axonal integrity. However, whether this favorable outcome observed in EAE is a consequence of an abrogated neuronal-specific pathophysiological mechanism, is yet to be defined. Here we show that, Cre-loxP-mediated neuron-specific deletion of ngr1 preserved axonal integrity, whereas its re-expression in ngr1-/- female mice potentiated EAE-axonopathy. As a corollary, myelin integrity was preserved under Cre deletion in ngr1flx/flx, retinal ganglion cell axons whereas, significant demyelination occurred in the ngr1-/- optic nerves following the re-introduction of NgR1. Moreover, Cre-loxP-mediated axon-specific deletion of ngr1 in ngr1flx/flx mice also demonstrated efficient anterograde transport of fluorescently-labeled ChTxβ in the optic nerves of EAE-induced mice. However, the anterograde transport of ChTxβ displayed accumulation in optic nerve degenerative axons of EAE-induced ngr1-/- mice, when NgR1 was reintroduced but was shown to be transported efficiently in the contralateral non- recombinant adeno-associated virus serotype 2-transduced optic nerves of these mutant mice. We further identified that the interaction between the axonal motor protein, Kinesin-1 and collapsin response mediator protein 2 (CRMP2) was unchanged upon Cre deletion of ngr1. Whereas, this Kinesin-1/CRMP2 association was reduced when NgR1 was re-expressed in the ngr1-/-optic nerves. Our data suggest that NgR1 governs axonal degeneration in the context of inflammatory-mediated demyelination through the phosphorylation of CRMP2 by stalling axonal vesicular transport. Moreover, axon-specific deletion of ngr1 preserves axonal transport mechanisms, blunting the induction of inflammatory demyelination and limiting the severity of EAE.

AB - We previously identified that ngr1 allele deletion limits the severity of experimental autoimmune encephalomyelitis (EAE) by preserving axonal integrity. However, whether this favorable outcome observed in EAE is a consequence of an abrogated neuronal-specific pathophysiological mechanism, is yet to be defined. Here we show that, Cre-loxP-mediated neuron-specific deletion of ngr1 preserved axonal integrity, whereas its re-expression in ngr1-/- female mice potentiated EAE-axonopathy. As a corollary, myelin integrity was preserved under Cre deletion in ngr1flx/flx, retinal ganglion cell axons whereas, significant demyelination occurred in the ngr1-/- optic nerves following the re-introduction of NgR1. Moreover, Cre-loxP-mediated axon-specific deletion of ngr1 in ngr1flx/flx mice also demonstrated efficient anterograde transport of fluorescently-labeled ChTxβ in the optic nerves of EAE-induced mice. However, the anterograde transport of ChTxβ displayed accumulation in optic nerve degenerative axons of EAE-induced ngr1-/- mice, when NgR1 was reintroduced but was shown to be transported efficiently in the contralateral non- recombinant adeno-associated virus serotype 2-transduced optic nerves of these mutant mice. We further identified that the interaction between the axonal motor protein, Kinesin-1 and collapsin response mediator protein 2 (CRMP2) was unchanged upon Cre deletion of ngr1. Whereas, this Kinesin-1/CRMP2 association was reduced when NgR1 was re-expressed in the ngr1-/-optic nerves. Our data suggest that NgR1 governs axonal degeneration in the context of inflammatory-mediated demyelination through the phosphorylation of CRMP2 by stalling axonal vesicular transport. Moreover, axon-specific deletion of ngr1 preserves axonal transport mechanisms, blunting the induction of inflammatory demyelination and limiting the severity of EAE.

KW - Axonal degeneration

KW - Collapsin response mediator protein 2

KW - Demyelination

KW - Experimental autoimmune encephalomyelitis

KW - Kinesin-1

KW - Nogo receptor 1

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U2 - 10.1523/JNEUROSCI.1760-18.2019

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JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

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