Possible Culprit Is Found for Lou Gehrig’s Disease

New York Times (August 29, 2011)-
THE HYPOTHESIS
An accumulation of neural proteins causes Lou Gehrig’s disease.
THE INVESTIGATOR
Dr. Teepu Siddique, Northwestern University.
Ever since the New York Yankees Hall of Famer Lou Gehrig benched himself in 1939, never to return to the game, the ailment that now bears his name has stoked dread in the American imagination.

Lou Gehrig’s disease — also known as amyotrophic lateral sclerosis, or A.L.S. — has afflicted well-known figures like the jazz great Charles Mingus, the physicist Stephen Hawking and the historian Tony Judt. The disease stems from the progressive deterioration of nerve cells, leading to a loss of control over voluntary muscles, difficulty breathing and swallowing, creeping paralysis and eventually death. There is no cure and no good treatment.

Scientists are still unsure exactly what causes most cases. But in the journal Nature last week, researchers at Northwestern University identified a possible culprit: a cellular housekeeping agent that normally helps cells to clear away proteins that are damaged or misfolded. When the housekeeper fails, proteins seem to aggregate inside nerve cells, which may be contributing to their destruction.

The finding has been hailed as a breakthrough by patient groups and scientists. The new work is “fueling great enthusiasm and interest,” said Dr. Amelie Gubitz of the National Institute of Neurological Disorders and Stroke, which helped finance the new work.

Still, it is far from clear that this is the wellspring of A.L.S. There are at least a dozen processes that also might contribute to the demise of motor nerve cells, Dr. Gubitz noted.

Scientists are investigating, for example, defects in cellular mitochondria, which are responsible for producing energy. They are researching problems with the neurotransmitter glutamate, which seems to overstimulate cells in A.L.S., causing toxicity. They are looking into abnormalities in the motor axons that run from nerve cell bodies to the junctions with muscles they cause to contract.

It’s possible that one of these might prove more important — or more amenable to treatment — than the others, Dr. Gubitz said. “We don’t know that yet,” she added. “We still need to pursue all of them.”

Yet there is growing evidence for the hypothesis that that defective protein clearance plays a pivotal role in A.L.S.

In the early 1990s, Dr. Siddique helped to discover mutations in a gene called SOD1 associated with some inherited forms of the disease. He and other researchers have since identified a variety of other mutations relevant to A.L.S. “The problem is that these mutations pertain to a very small number of patients,” he said in an interview.
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