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The Journal of Neuroscience, January 1, 2003, 23(1):43-51
Global Loss of Na,K-ATPase and Its Nitric Oxide-Mediated
Regulation in a Transgenic Mouse Model of Amyotrophic Lateral
Sclerosis
Dorette Z.
Ellis,
Jason
Rabe, and
Kathleen J.
Sweadner
The Neuroscience Center, Massachusetts General Hospital,
Charlestown, Massachusetts 02129
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 ( 1, 2, 3) were reduced, and the global 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 , but not  ,
subunits. Together, these observations are consistent with selective
degradation of the 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.
Key words:
Na,K-ATPase; SOD1; amyotrophic lateral sclerosis; neurodegeneration; spinal cord; nitric oxide
Copyright © 2003 Society for Neuroscience 0270-6474/03/23143-09$05.00/0
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