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 ALS — 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 ALS. There are at least a dozen processes that also might contribute to the demise of motor nerve cells, 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 ALS, 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, 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 ALS.
In the early 1990s, Dr. Teepu Siddique of Northwestern University 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 ALS.
"The problem is that these mutations pertain to a very small number of patients," he said in an interview.
Only 5 to 10 percent of ALS cases are inherited. The rest are sporadic, arising without warning in patients even though they do not have these mutations.
"The holy grail of the field has been to find a point of molecular convergence" that might explain all types of ALS, Siddique said.
The significance of the new report is that he and his team described a cellular problem that appears in both inherited and noninherited forms of the disease.
In families with inherited ALS, the researchers discovered mutations in a gene that produces a protein called ubiquilin 2. It normally helps cells dispose of and recycle other proteins that are misfolded, damaged or no longer needed.
At the same time, Siddique and his colleagues reviewed autopsy tissue from several dozen patients without the mutations in the gene for ubiquilin 2. Remarkably, they found that in every case, ubiquilin 2 nonetheless had accumulated abnormally in spinal cord tissue. In patients with ALS and dementia, the protein had accumulated in the brain, as well.
"It was clear that this particular protein was misregulated, and its function was probably impaired," not only in the cases with the genetic mutations but across the board, Siddique said.
This finding suggests that researchers might discover a way to treat a broad range of ALS patients by singling out ubiquilin 2 or the chemical pathway it is part of.
But many daunting questions remain. What makes this housekeeping protein spontaneously misfold and accumulate in cases of noninherited ALS? And how important, ultimately, is its aberrant behavior to the overall development or progression of the disease?
At least one other protein is known to go awry in all noninherited and virtually all inherited forms of ALS, noted Dr. Raymond Roos, a neurologist at the University of Chicago. That protein, called TDP43, normally plays a role in splicing and regulating molecules of RNA, which are then used to create new proteins.
"So is one of these defective proteins more important than the other in the development of ALS? Are there five others that are important, as well?" Roos asked. "These are questions that still need to be answered."
The mysteries of ALS mirror to some degree those of other neurodegenerative diseases, like Alzheimer’s. There, too, misfolded, accumulated proteins are hallmarks of the pathology — and sources of contention.
Some researchers argue that aggregations of beta-amyloid proteins are the key culprits. Others focus on tau proteins, which also accumulate abnormally. Still others suggest that protein aggregates are markers, rather than root causes, of dysfunction.
In ALS, "we can look at autopsy samples and see what’s happened in the end," Dr. Lucie Bruijn of the ALS Association said. "But in living people, it’s difficult to figure out what the beginning looks like."