Pouring a bucket of ice water over one’s head may seem like a distant summer memory. But although the “ice bucket challenge” craze has died down, public awareness of amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, has never been stronger. The viral video campaign raised $115 million from more than 3 million donors for the ALS Association. In one month, from July 29 to August 29, donors raised $100.9 million, compared with $2.8 million during the same period the previous year.

In early October, the ALS Association began spending that money. It approved $21.7 million of funding for six programs and initiatives by groups that include the academic-industry partnership ALS Accelerated Therapeutics, the New York Genome Center, three California labs that form the Neuro Collaborative, and Project MinE, which will map the genomes of 15,000 people with ALS (about 10 percent of ALS patients have a family member with the disease). The grants focus on developing gene therapies for common ALS genes and exploring approaches to counter two major contributors to the disease, the inflammation of nervous tissue and misfolded proteins in brain cells that control movement.

These efforts may not only someday lead to new treatments, but may also point to the cause of ALS. At the level of basic research, scientists do not have a dominant theory from which to work, notes Tom Jessell, a neuroscientist and co-director of Columbia University’s new Zuckerman Mind Brain Behavior Institute. Jessell is also the chair of the research advisory board of Project ALS, a nonprofit that identifies and funds ALS research.

One clue to a better theory—and possibly new avenues of treatment—may lie in an intriguing detail about ALS: some nerve cells die from the disease, but certain others do not. ALS destroys nerve cells in the brain and spinal cord that control muscle movement. Control of arms and legs typically weakens first, followed by other muscles, such as those used for breathing and eating. In the last stages of ALS, which is typically fatal in two to five years after diagnosis, patients have lost most of their motor neurons. Yet many patients, even in late stages, can still move their eyes and sometimes control the sphincter and a few other muscles.

This is the case in ALS patients such as Steve Gleason, a former NFL football player with the New Orleans Saints who retired in 2008 after eight seasons. Gleason was diagnosed with ALS in 2011. Today he cannot move or speak and needs assistance to breathe and eat. Gleason’s eye muscles, however, still function and allow him to communicate. He uses his eyes to control a “speech-generating device” in a computer tablet attached to his wheelchair.

(Stephen Hawking, the renowned English physicist who was diagnosed with ALS at 21, appears to have a rare form of ALS that progresses very, very slowly: he can communicate using a speech-generating device controlled by twitching his cheek muscle.)

The longevity of eye muscles in ALS patients suggests some motor neurons are more vulnerable to the disease than others. This difference opens up some intriguing possibilities. Knowing what makes certain motor neurons resistant to the disease might mean that other motor neurons could be saved.

An important clue may lie in the wiring of the motor neurons. Those vulnerable to ALS connect to specialized sensory neurons and “receive continuous excitation from other neurons that release glutamate,” an important neurotransmitter that excites motor neurons and triggers muscle movement, explains neuroscientist George Mentis of the Center for Motor Neuron Biology and Disease at Columbia University.  

Eye and sphincter motor neurons, however, do not receive synaptic connections from these specialized sensory neurons and instead get their signals from different neurons. They also “receive less glutamate from yet different sources, ultimately triggering muscle movement in a different way,” Mentis says. Specifically, the ALS-resistant neurons  receive more discrete, specific bursts of the chemical instead of a continuous flow. Sustained exposure to glutamate may cause an over-accumulation of calcium, which harms cells.

Evidence for glutamate’s role comes from the only approved treatment for ALS: a drug called Rilutek that decreases the body’s glutamate levels and can slow progression of the disease for a few months.
Even if glutamate is not the ultimate cause of ALS—other theories include free-radical damage and various gene and protein defects—research in this area “can give important insights into better understanding the disease,” says Mentis, whose lab studies the cellular and neural circuitry involved in spinal motor control during normal behavior and neurodegenerative conditions.

A cure for ALS is most likely many years away, considering that the costs of large-scale clinical trials reach upwards of $200 million. Nevertheless, scientists should be on the cusp of developing new medicines to slow the progression of ALS, perhaps within seven to 10 years, Jessell estimates.

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