A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis.
In the 16 years since mutations to copper, zinc superoxide dismutase (SOD1) were first linked to familial amyotrophic lateral sclerosis (ALS), a multitude of apparently contradictory results have prevented any general consensus to emerge about the mechanism of toxicity. A decade ago, we showed that the loss of zinc from SOD1 results in the remaining copper in SOD1 to become extremely toxic to motor neurons in culture by a mechanism requiring nitric oxide. The loss of zinc causes SOD1 to become more accessible, more redox reactive, and a better catalyst of tyrosine nitration. Although SOD1 mutant proteins have a modestly reduced affinity for zinc, wild-type SOD1 can be induced to lose zinc by dialysis at slightly acidic pH. Our zinc-deficient hypothesis offers a compelling explanation for how mutant SOD1s have an increased propensity to become selectively toxic to motor neurons and also explains how wild-type SOD1 can be toxic in nonfamilial ALS patients. One critical prediction is that a therapeutic agent directed at zinc-deficient mutant SOD1 could be even more effective in treating sporadic ALS patients. Although transgenic mice experiments have yielded contradictory evidence to the zinc-deficient hypothesis, we will review more recent studies that support a role for copper in ALS. A more careful examination of the role of copper and zinc binding to SOD1 may help counter the growing disillusion in the ALS field about understanding the pathological role of SOD1.
Trumbull
Kari A
KA
Linus Pauling Institute, Department of Biochemistry and Biophysics, Corvallis, Oregon 97331, USA.
Beckman
Joseph S
JS
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology*; D000818:Animals; D003300:Copper / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009046:Motor Neurons / Q000502:physiology*; D011487:Protein Conformation; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*
D003300:Copper; D013482:Superoxide Dismutase