TY - JOUR
T1 - Global loss of Na,K-ATPase and its nitric oxide-mediated regulation in a transgenic mouse model of amyotrophic lateral sclerosis
AU - Ellis, Dorette Z.
AU - Rabe, Jason
AU - Sweadner, Kathleen J.
PY - 2003/1/1
Y1 - 2003/1/1
N2 - Na,K-ATPase plays a critical role in energy metabolism and ion fluxes. Its loss was investigated in the G93A mouse model of amyotrophic lateral sclerosis (ALS) in which the mutation of Cu/Zn superoxide dismutase (SOD1) is thought to lead to aberrant oxidative damage. Observed losses in spinal cord Na,K-ATPase activity exceeded all expectations. All three catalytic subunit isoforms (α1, α2, α3) were reduced, and the global α subunit loss affected not just neurons, glia, and myelinated axon tracts but even ependymal and pial membranes. Decreases in Na,K-ATPase activity were greater than losses of protein, and there were losses of Na,K-ATPase α, but not β, subunits. Together, these observations are consistent with selective degradation of the α subunit after damage. Overexpression of normal SOD1 does not cause ALS-like symptoms, but it has other known pathological effects. In transgenic mice overexpressed normal human SOD1 had a smaller but still considerable effect on Na,K-ATPase. Furthermore, the nitric oxide-mediated regulatory pathway for Na,K-ATPase inhibition was undetectable in spinal cord tissue slices from mice overexpressing either mutant or normal human SOD1. Na,K-ATPase activity did not respond to nitric oxide donors, and the free radical-dependent step of the pathway could not be bypassed by the addition of the downstream protein kinase G activator, 8-Br-cGMP. The data demonstrate that Na,K-ATPase is vulnerable to aberrant SOD1 activity, making it a potential contributing factor in disease pathology. Moreover, the global cellular distribution of Na,K-ATPase loss indicates that SOD1 overexpression is far-reaching in its pathological effects.
AB - Na,K-ATPase plays a critical role in energy metabolism and ion fluxes. Its loss was investigated in the G93A mouse model of amyotrophic lateral sclerosis (ALS) in which the mutation of Cu/Zn superoxide dismutase (SOD1) is thought to lead to aberrant oxidative damage. Observed losses in spinal cord Na,K-ATPase activity exceeded all expectations. All three catalytic subunit isoforms (α1, α2, α3) were reduced, and the global α subunit loss affected not just neurons, glia, and myelinated axon tracts but even ependymal and pial membranes. Decreases in Na,K-ATPase activity were greater than losses of protein, and there were losses of Na,K-ATPase α, but not β, subunits. Together, these observations are consistent with selective degradation of the α subunit after damage. Overexpression of normal SOD1 does not cause ALS-like symptoms, but it has other known pathological effects. In transgenic mice overexpressed normal human SOD1 had a smaller but still considerable effect on Na,K-ATPase. Furthermore, the nitric oxide-mediated regulatory pathway for Na,K-ATPase inhibition was undetectable in spinal cord tissue slices from mice overexpressing either mutant or normal human SOD1. Na,K-ATPase activity did not respond to nitric oxide donors, and the free radical-dependent step of the pathway could not be bypassed by the addition of the downstream protein kinase G activator, 8-Br-cGMP. The data demonstrate that Na,K-ATPase is vulnerable to aberrant SOD1 activity, making it a potential contributing factor in disease pathology. Moreover, the global cellular distribution of Na,K-ATPase loss indicates that SOD1 overexpression is far-reaching in its pathological effects.
KW - Amyotrophic lateral sclerosis
KW - Na,K-ATPase
KW - Neurodegeneration
KW - Nitric oxide
KW - SOD1
KW - Spinal cord
UR - http://www.scopus.com/inward/record.url?scp=0037221596&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.23-01-00043.2003
DO - 10.1523/jneurosci.23-01-00043.2003
M3 - Article
C2 - 12514200
AN - SCOPUS:0037221596
SN - 0270-6474
VL - 23
SP - 43
EP - 51
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 1
ER -