The control of reactive oxygen species production by SHP-1 in oligodendrocytes

Ross C. Gruber, Daria Larocca, Scott B. Minchenberg, George P. Christophi, Chad A. Hudson, Alex K. Ray, Bridget Shafit-Zagardo, Paul T. Massa

Research output: Contribution to journalArticle

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Abstract

We have previously described reduced myelination and corresponding myelin basic protein (MBP) expression in the central nervous system of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) deficient motheaten (me/me) mice compared with normal littermate controls. Deficiency in myelin and MBP expression in both brains and spinal cords of motheaten mice correlated with reduced MBP mRNA expression levels in vivo and in purified oligodendrocytes in vitro. Therefore, SHP-1 activity seems to be a critical regulator of oligodendrocyte gene expression and function. Consistent with this role, this study demonstrates that oligodendrocytes of motheaten mice and SHP-1-depleted N20.1 cells produce higher levels of reactive oxygen species (ROS) and exhibit corresponding markers of increased oxidative stress. In agreement with these findings, we demonstrate that increased production of ROS coincides with ROS-induced signaling pathways known to affect myelin gene expression in oligodendrocytes. Antioxidant treatment of SHP-1-deficient oligodendrocytes reversed the pathological changes in these cells, with increased myelin protein gene expression and decreased expression of nuclear factor (erythroid-2)-related factor 2 (Nrf2) responsive gene, heme oxygenase-1 (HO-1). Furthermore, we demonstrate that SHP-1 is expressed in human white matter oligodendrocytes, and there is a subset of multiple sclerosis subjects that demonstrate a deficiency of SHP-1 in normal-appearing white matter. These studies reveal critical pathways controlled by SHP-1 in oligodendrocytes that relate to susceptibility of SHP-1-deficient mice to both developmental defects in myelination and to inflammatory demyelinating diseases.

Original languageEnglish (US)
Pages (from-to)1753-1771
Number of pages19
JournalGLIA
Volume63
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Oligodendroglia
Reactive Oxygen Species
Myelin Basic Protein
Myelin Sheath
Gene Expression
SH2 Domain-Containing Protein Tyrosine Phosphatases
Myelin Proteins
Protein Phosphatase 1
Heme Oxygenase-1
Protein Tyrosine Phosphatases
Critical Pathways
Demyelinating Diseases
Regulator Genes
Multiple Sclerosis
Spinal Cord
Oxidative Stress
Central Nervous System
Antioxidants
Messenger RNA
Brain

Keywords

  • Inflammation
  • Multiple sclerosis
  • Myelin
  • Normal-appearing white matter
  • Oxidative stress

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

Gruber, R. C., Larocca, D., Minchenberg, S. B., Christophi, G. P., Hudson, C. A., Ray, A. K., ... Massa, P. T. (2015). The control of reactive oxygen species production by SHP-1 in oligodendrocytes. GLIA, 63(10), 1753-1771. https://doi.org/10.1002/glia.22842

The control of reactive oxygen species production by SHP-1 in oligodendrocytes. / Gruber, Ross C.; Larocca, Daria; Minchenberg, Scott B.; Christophi, George P.; Hudson, Chad A.; Ray, Alex K.; Shafit-Zagardo, Bridget; Massa, Paul T.

In: GLIA, Vol. 63, No. 10, 01.10.2015, p. 1753-1771.

Research output: Contribution to journalArticle

Gruber, RC, Larocca, D, Minchenberg, SB, Christophi, GP, Hudson, CA, Ray, AK, Shafit-Zagardo, B & Massa, PT 2015, 'The control of reactive oxygen species production by SHP-1 in oligodendrocytes', GLIA, vol. 63, no. 10, pp. 1753-1771. https://doi.org/10.1002/glia.22842
Gruber RC, Larocca D, Minchenberg SB, Christophi GP, Hudson CA, Ray AK et al. The control of reactive oxygen species production by SHP-1 in oligodendrocytes. GLIA. 2015 Oct 1;63(10):1753-1771. https://doi.org/10.1002/glia.22842
Gruber, Ross C. ; Larocca, Daria ; Minchenberg, Scott B. ; Christophi, George P. ; Hudson, Chad A. ; Ray, Alex K. ; Shafit-Zagardo, Bridget ; Massa, Paul T. / The control of reactive oxygen species production by SHP-1 in oligodendrocytes. In: GLIA. 2015 ; Vol. 63, No. 10. pp. 1753-1771.
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