ApoE isoform-specific regulation of regeneration in the peripheral nervous system

Laura H Comley, Heidi R Fuller, Thomas M Wishart, Chantal A Mutsaers, Derek Thomson, Ann K Wright, Richard R Ribchester, Glenn E Morris, Simon H Parson, Karen Horsburgh, Thomas H Gillingwater

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Apolipoprotein E (apoE) is a 34 kDa glycoprotein with three distinct isoforms in the human population (apoE2, apoE3 and apoE4) known to play a major role in differentially influencing risk to, as well as outcome from, disease and injury in the central nervous system. In general, the apoE4 allele is associated with poorer outcomes after disease or injury, whereas apoE3 is associated with better responses. The extent to which different apoE isoforms influence degenerative and regenerative events in the peripheral nervous system (PNS) is still to be established, and the mechanisms through which apoE exerts its isoform-specific effects remain unclear. Here, we have investigated isoform-specific effects of human apoE on the mouse PNS. Experiments in mice ubiquitously expressing human apoE3 or human apoE4 on a null mouse apoE background revealed that apoE4 expression significantly disrupted peripheral nerve regeneration and subsequent neuromuscular junction re-innervation following nerve injury compared with apoE3, with no observable effects on normal development, maturation or Wallerian degeneration. Proteomic isobaric tag for relative and absolute quantitation (iTRAQ) screens comparing healthy and regenerating peripheral nerves from mice expressing apoE3 or apoE4 revealed significant differences in networks of proteins regulating cellular outgrowth and regeneration (myosin/actin proteins), as well as differences in expression levels of proteins involved in regulating the blood-nerve barrier (including orosomucoid 1). Taken together, these findings have identified isoform-specific roles for apoE in determining the protein composition of peripheral nerve as well as regulating nerve regeneration pathways in vivo.

Original languageEnglish
Pages (from-to)2406-2421
Number of pages16
JournalHuman Molecular Genetics
Volume20
Issue number12
Early online date11 Apr 2011
DOIs
Publication statusPublished - 15 Jun 2011

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Apolipoprotein E3
Apolipoprotein E4
Peripheral Nervous System
Apolipoproteins E
Regeneration
Protein Isoforms
Peripheral Nerves
Nerve Regeneration
Wounds and Injuries
Proteins
Blood-Nerve Barrier
Apolipoprotein E2
Wallerian Degeneration
Orosomucoid
Neuromuscular Junction
Myosins
Proteomics
Actins
Glycoproteins
Central Nervous System

Keywords

  • animals
  • apolipoproteins E
  • axons
  • blotting, Western
  • electrophysiology
  • humans
  • immunohistochemistry
  • mice
  • mice, inbred C57BL
  • mice, knockout
  • microscopy, electron, transmission
  • microscopy, fluorescence
  • nerve regeneration
  • orosomucoid
  • peripheral nervous system
  • protein isoforms
  • proteomics
  • spectrometry, mass
  • tandem mass spectrometry
  • matrix-assisted laser
  • desorption-ionization

Cite this

Comley, L. H., Fuller, H. R., Wishart, T. M., Mutsaers, C. A., Thomson, D., Wright, A. K., ... Gillingwater, T. H. (2011). ApoE isoform-specific regulation of regeneration in the peripheral nervous system. Human Molecular Genetics, 20(12), 2406-2421. https://doi.org/10.1093/hmg/ddr147

ApoE isoform-specific regulation of regeneration in the peripheral nervous system. / Comley, Laura H; Fuller, Heidi R; Wishart, Thomas M; Mutsaers, Chantal A; Thomson, Derek; Wright, Ann K; Ribchester, Richard R; Morris, Glenn E; Parson, Simon H; Horsburgh, Karen; Gillingwater, Thomas H.

In: Human Molecular Genetics, Vol. 20, No. 12, 15.06.2011, p. 2406-2421.

Research output: Contribution to journalArticle

Comley, LH, Fuller, HR, Wishart, TM, Mutsaers, CA, Thomson, D, Wright, AK, Ribchester, RR, Morris, GE, Parson, SH, Horsburgh, K & Gillingwater, TH 2011, 'ApoE isoform-specific regulation of regeneration in the peripheral nervous system', Human Molecular Genetics, vol. 20, no. 12, pp. 2406-2421. https://doi.org/10.1093/hmg/ddr147
Comley LH, Fuller HR, Wishart TM, Mutsaers CA, Thomson D, Wright AK et al. ApoE isoform-specific regulation of regeneration in the peripheral nervous system. Human Molecular Genetics. 2011 Jun 15;20(12):2406-2421. https://doi.org/10.1093/hmg/ddr147
Comley, Laura H ; Fuller, Heidi R ; Wishart, Thomas M ; Mutsaers, Chantal A ; Thomson, Derek ; Wright, Ann K ; Ribchester, Richard R ; Morris, Glenn E ; Parson, Simon H ; Horsburgh, Karen ; Gillingwater, Thomas H. / ApoE isoform-specific regulation of regeneration in the peripheral nervous system. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 12. pp. 2406-2421.
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AU - Comley, Laura H

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AU - Wishart, Thomas M

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AU - Thomson, Derek

AU - Wright, Ann K

AU - Ribchester, Richard R

AU - Morris, Glenn E

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AB - Apolipoprotein E (apoE) is a 34 kDa glycoprotein with three distinct isoforms in the human population (apoE2, apoE3 and apoE4) known to play a major role in differentially influencing risk to, as well as outcome from, disease and injury in the central nervous system. In general, the apoE4 allele is associated with poorer outcomes after disease or injury, whereas apoE3 is associated with better responses. The extent to which different apoE isoforms influence degenerative and regenerative events in the peripheral nervous system (PNS) is still to be established, and the mechanisms through which apoE exerts its isoform-specific effects remain unclear. Here, we have investigated isoform-specific effects of human apoE on the mouse PNS. Experiments in mice ubiquitously expressing human apoE3 or human apoE4 on a null mouse apoE background revealed that apoE4 expression significantly disrupted peripheral nerve regeneration and subsequent neuromuscular junction re-innervation following nerve injury compared with apoE3, with no observable effects on normal development, maturation or Wallerian degeneration. Proteomic isobaric tag for relative and absolute quantitation (iTRAQ) screens comparing healthy and regenerating peripheral nerves from mice expressing apoE3 or apoE4 revealed significant differences in networks of proteins regulating cellular outgrowth and regeneration (myosin/actin proteins), as well as differences in expression levels of proteins involved in regulating the blood-nerve barrier (including orosomucoid 1). Taken together, these findings have identified isoform-specific roles for apoE in determining the protein composition of peripheral nerve as well as regulating nerve regeneration pathways in vivo.

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KW - blotting, Western

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KW - immunohistochemistry

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KW - mice, knockout

KW - microscopy, electron, transmission

KW - microscopy, fluorescence

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KW - orosomucoid

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KW - protein isoforms

KW - proteomics

KW - spectrometry, mass

KW - tandem mass spectrometry

KW - matrix-assisted laser

KW - desorption-ionization

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JO - Human Molecular Genetics

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