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The control of reactive oxygen species production by SHP-1 in oligodendrocytes
Ross C Gruber1,2, Daria LaRocca3, Scott B Minchenberg3
1Department of Neurology, SUNY Upstate Medical University, Syracuse, New York.
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.
Insights
Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) deficiency impairs myelin basic protein (MBP) expression in mice by increasing oxidative stress in oligodendrocytes. Restoring SHP-1 function or using antioxidants reverses these effects, suggesting a role in demyelinating diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Reduced myelination and myelin basic protein (MBP) expression are observed in the central nervous system of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) deficient motheaten (me/me) mice.
- SHP-1 deficiency correlates with reduced MBP mRNA levels in vivo and in vitro, indicating SHP-1 is a critical regulator of oligodendrocyte gene expression and function.
Purpose of the Study:
- To investigate the role of SHP-1 in regulating oligodendrocyte function and myelination.
- To explore the impact of SHP-1 deficiency on oxidative stress pathways in oligodendrocytes.
- To determine the potential involvement of SHP-1 in human demyelinating diseases like multiple sclerosis.
Main Methods:
- Comparison of myelination and MBP expression in SHP-1 deficient (motheaten) mice and wild-type littermates.
- Assessment of reactive oxygen species (ROS) production and oxidative stress markers in oligodendrocytes from motheaten mice and SHP-1-depleted N20.1 cells.
- Evaluation of antioxidant treatment effects on SHP-1-deficient oligodendrocytes, including gene expression analysis (MBP, HO-1, Nrf2).
Main Results:
- SHP-1 deficient oligodendrocytes exhibit increased ROS production and oxidative stress markers.
- Increased ROS correlates with ROS-induced signaling pathways affecting myelin gene expression.
- Antioxidant treatment reverses pathological changes in SHP-1 deficient oligodendrocytes, restoring MBP expression and decreasing HO-1 expression.
Conclusions:
- SHP-1 plays a critical role in regulating oligodendrocyte oxidative stress and myelin gene expression.
- SHP-1 deficiency in oligodendrocytes leads to impaired myelination and increased susceptibility to demyelinating conditions.
- SHP-1 deficiency is observed in human white matter oligodendrocytes of a subset of multiple sclerosis patients, suggesting a role in the disease.
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