SOD1 And Metal Ion's, And Their Relation To ALS

SOD1 is an enzyme whose full name is Super Oxide Dismutase. It's function is to catalyze the detoxification of the superoxide anion, thus preventing damaged associated with this molecule. Another function of this enzyme is to bind free copper in the body. It is hard to tell which is the primary function of the enzyme. This is because there are other enzymes that can catalyze the detoxification of super oxide free radicals, and mutant SOD1's still continue with this function. There is always a certain amount of redundancy within biological systems, but the mutants of this enzyme that cause the most damage may do so due to malfunction within their copper binding processes.

Many oxidative reactions in the body are catalyzed by transition metals such as iron, copper, and manganese. These metals have multiple valence states allowing them to alternately donate or accept electrons. For instance iron can either be ferric or ferrous, that is the ion is either Fe⁺³ , or Fe⁺² . This ability allows them to promote the formation of free radicals. A major mechanism of free radical formation is via the Fenton Reaction:

H₂O₂ + Fe⁺² --> ^.OH + OH^- + Fe⁺³

SOD1 catalyzes the detoxification of superoxide free radicals via the following equation:

^.O₂^- + ^.O₂^- --> H₂O₂ + O₂

One of the things SOD1 does by catalyzing the detoxification of superoxide free radicals is preventing the free radicals from reacting with nitric acid to form peroxynitrite.

^-O₂^- + NO^. --> ONOO^-

This is important because peroxynitrite can be protonated to form peroxynitrous acid. Peroxynitrous acid will may then decompose releasing a hydroxyl free radical ( ^.OH ). Additionally this is important because peroxynitrite will also react with tyrosine molecules generating nitrotyrosine. Nitrotyrosine formation may promote degeneration in cytoskeletal molecules, and of equal importance, has the potential to impair tyrosine trophic factor receptors. This will cause a loss of the extremely important trophic effect.

Peroxynitrite has other effects as well, oxidizing thiols and inhibiting portions of the mitochondrial transport chain. By disrupting the mitochondrial transport chain, peroxynitrite limits the cells production of ATP, the primary energy source. This will have obvious detrimental effects on the neurons in question eventually leading to neural starvation if pronounced enough. The extent of mitochondrial disruption due to peroxynitrite formation is not known. In the absence of direct methodologies used to detect peroxynitrite levels, on test measured one of it's potential targets, glutathione (a thiol). The experimenters found that the thiol was not significantly affected. This does not however preclude the possibility that peroxynitrite may detrimentally affect the neuron as stated.

The trophic effect is mediated by neurotrophic factors that act in a retrograde manner. These signals travel upward toward the cell body from the axons. Many of these signals tell the neuron that they actually synapse with something else and are thus useful and necessary. The absence of these signals may cause neurons to atrophy. In the CNS both NGF (Nerve growth factor) and BDNF (brain derived neurotrophic factor) increase survival of and rescue injured cholinergic neurons after injury or age related damage. These signals are up regulated by glutamate receptors in the CNS. However some researchers believe that little NGF or other neurotrophins are produced by the CNS glial cells after injury. This lack of neurotrophic factor may be the reason that CNS cells have a difficult time of recovering from injury, and often times instead of repair of damaged neurons, "rewiring" of existing circuitry is used to compensate for injury.

Hydroxyl and superoxide free radicals are toxic because of the way they interact with other biological compounds. They damage certain cellular membranes (like mitochondrial membranes) by lipid peroxidation, and they also damage glutamate transporters. Hydroxyl free radicals are also known to damage SOD1.

Damaged glutamate transporters are in part responsible for a high concentration of extracellular glutamate. This increase in extracellular glutamate concentration leads to an increase in intracellular calcium levels, often times resulting in excitotoxic damage to the neuron.

This all fits very nicely into what is observed during ALS. An increase in the free radical population detrimentally effects neurons by damaging cell membranes, decreasing the effectiveness of some enzymes and damaging glutamate transporters. In addition by forming nitrotyrosine the degeneration of certain cytskeletal molecules is promoted and tyrosine trophic factor receptors are inhibited. The disruption of mitochondrial membrane reduces the amount of ATP produced by the cell, adversly affecting it. By damaging the glutamate transporters an increase in intracellular calcium is observed. High concentrations of intracellular calcium are known to mediate the breakdown of certain cytoskeletal structures. This breakdown is facilitated by the effects of nitrotyrosine. The breakdown of the cytoskeletal structures most likely leads to the neuronal shrinkage seen during ALS. In addition the damage to the tyrosine trophic factor receptors, coupled with the damage to the glutamate transporters, help to stem any sort of relief offered by the little neurotrophic factor produced in the brain. If this is indeed the case then the neurons shrink and eventually atrophy.

It is interesting to note that the mutant SOD1 genes characteristic of FALS, still carry out their dismutase function. It is thought that the mutation effects the way the enzyme binds copper. Perhaps it binds the copper but does so in such a way that the metal is able to inadvertently catalyze toxic reactions. This would lead to an increase in free radicals with the above mentioned results. Biochemical studies done by Wiedau-Pazos, et.al. show that mutant SOD1 genes may be more likely to produce toxic substances like the hydroxyl free radical. It however is not clear whether these effects contribute significantly to ALS.

Much of this article is based on work done by David R. Borchelt, et al.