Mutated protein contributes to Lou Gehrig's

By: Sam Ohmer

Posted: 11/19/09

A new finding by researchers at Hopkins's School of Medicine has elucidated a little-known molecular pathway in the development of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.

The study by Kevin Chen, Lee Martin and Frances Northington has discovered a malfunction mechanism that they believe can and does contribute to the development of ALS.

The mechanism involves over expression of one protein in particular: inducible nitric oxide synthase (iNOS or NOS2). This protein seems to be up regulated, at least in part, by a mutated form of the gene encoding for the superoxide dismutase-1 (SOD1) enzyme.

Inducible nitric oxide synthase, as its name suggests, is an enzyme that synthesizes nitric oxide. Nitric oxide in the brain serves a variety of functions, one of which is its role as a freely diffusing neurotransmitter.

However, nitric oxide (NO) can also react with a form of oxygen called the superoxide anion (O2-) to form highly reactive and destructive products. Usually the superoxide anion is processed into a less harmful form by the SOD1 protein.

When SOD1 is not working properly, highly reactive products of nitric oxide and the superoxide anion can accumulate and cause extensive damage. These products, such as the peroxynitrite ion, damage cells by attacking key molecular building blocks like amino acids, lipids and nucleic acids.

"Motor neurons, which are uniquely vulnerable in ALS, are also unique in that they express . . . very, very low levels [of] iNOS normally, even without any ALS pathology," Martin said. "Furthermore, and quite interestingly, even before symptoms of ALS emerge at a macro, observable level, the level of iNOS expressed in some cells increases noticeably, most specifically in the motor neurons of the spinal cord and the brainstem."

Later on, however, the greatest up regulation of iNOS is not in these cells, but rather in some microglia and astrocytes. Microglia and astrocytes are two types of neuronal support cells. Usually, they help to protect neurons or deliver nutrients and neurotransmitter precursors to neurons.

In this particular mechanism of ALS, however, these support cells might also be passing onto neurons something they don't need: damage caused by reactive nitrogen and oxygen species.

Furthermore, the greatest accumulations of iNOS were found in the mitochondria of affected cells. The inner compartments of mitochondria supply most of the cell's energy in the form of ATP. Some of the reactions involved produce oxygen species that may act as targets for aberrant iNOS behavior.

The damage caused by the mutated SOD1 and subsequent up-regulation of the iNOS protein is selective mostly for motor neurons. These are the neurons that send their signals to muscles, telling them when and how to contract or relax. As the disease inevitably progresses, symptoms worsen. The first signs are weakness of the muscles, muscle degeneration and spastic movements.

The later stages of ALS are characterized not only by the worsening of these symptoms, but also by paralysis of movement, of speech, of swallowing and even, eventually, of breathing. This degeneration occurs in just three to five years.

Most patients will "die because they become paralyzed and cannot swallow or breathe," Lee Martin, one of the scientists who worked on this research, said. These last years are highly unpleasant ones, and there exist few to no medications or treatments that can even address, let alone actually treat or cure, the symptoms.

Scientists like Chen, Martin and Northington are highly excited by their findings. "Our study shows that this up-regulation of iNOS contributes to the development of pathology in ALS and that blocking iNOS has significant effects on the development and duration of disease," Martin said.

At least within the mouse model used to study ALS, drugs that act as inhibitors of iNOS's function can delay the onset of ALS. They also extend the life expectancy of ALS-suffering mice, suggesting that in the future, similarly functioning drugs may prove to be effective pharmacological therapies and treatments.

It is thought that 10 percent of all cases of ALS have an inherited genetic component, with 20 percent of these involving the SOD1 mutation. As a result, this study, and other complementary ones, are crucial in our development of a deeper and more useful understanding of how ALS develops.

In pursuit of that purpose, scientists will continue their already decade-long investigation by searching for more answers.

Future investigations will study why normal, healthy motor neurons express iNOS, whether similar mutations in other mouse models exhibit the same patterns of disease development, which drugs will best inhibit the development of the disease, the effects of such drugs on human tissues and whether these drugs will ever be viable human treatments.

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