New Hope for Neuron Protection

A drug developed to treat Lou Gehrig's disease undergoes clinical trials.

Finding a cure for amyotrophic lateral sclerosis (ALS)--also known as Lou Gehrig's disease--has been a frustrating and elusive quest. Even after decades of research, the biological roots of ALS are only partially understood. Now a new form of treatment offers fresh hope.

Trophos, a company based in Marseilles, France, has discovered a drug compound that appears to protect neurons from the effects of ALS, a rapidly debilitating degeneration of motor neurons in the brain and spinal cord. These effects lead to muscle atrophy and, ultimately, complete loss of motor control. The company's researchers have found that a compound named olesoxime promotes survival and regeneration of neurons deprived of neurotrophic factors--proteins essential for maintaining healthy neurons. This deprivation is similar to what occurs in the neurons of ALS patients.

The company is currently conducting Phase II clinical trials to test the drug's efficacy in ALS patients. Although the compound's mechanism of action isn't exactly clear, researchers believe it acts like a molecular "stopper," preventing motor neurons from dying off by blocking a key structure that triggers the degeneration of nerve cell mitochondria.

For the past decade, researchers have increasingly focused on mitochondria as a potential target for treating ALS and other neurodegenerative diseases. Often referred to as the powerhouse of cells, mitochondria churn out ATP, a nucleotide that transfers the energy needed by cells. Researchers have found that in ALS patients, something causes the mitochondria to swell up and burst. Scientists believe that the accumulation of dead mitochondria deprives neurons of energy. This causes the neurons to die and thus lose their connection with associated muscles.

Story continues below

It's unclear how mitochondria become dysfunctional in ALS patients in the first place, but over the past two years, scientists have identified a tiny pore within a membrane that may act as a fatal floodgate, letting in unwanted molecules that destabilize mitochondria. This gateway, called the mitochondrial permeability transition pore (mPTP), forms when two proteins within the inner and outer membrane come together. The resulting channel lets in a flood of calcium and other molecules, the source of the swelling in mitochondria.

Lee Martin, a professor of pathology and neuroscience at Johns Hopkins University in Baltimore, who was not involved with the research, says this mitochondrial opening may have evolved in order to get rid of damaged cells and make way for new, healthy cells. However, in diseases such as ALS, membrane proteins may come together more often, and the resulting pore may stay open longer than normal, causing otherwise healthy mitochondria and neurons to die off. "Normally this pore is in a state of flicker," says Martin. "However, in disease states, this flicker may be transformed into a more permanent, more stable opening, and this is really bad."