You Have 24 Hours: The struggles of treating amyotrophic lateral sclerosis (ALS)

Last summer, social media users across the nation began dumping frigid water on their heads, filming the action, and sharing it online. Rapidly, 1.2 million videos accumulated on Facebook — the ALS Ice Bucket Challenge had gone viral. The rules for the task were simple: once challenged, a participant had 24 hours to decide whether to pour a bucket of ice water over his head, or to donate money to the ALS Association. The campaign successfully increased public awareness of the disease, drawing approximately 260,000 new donors and millions of dollars to help fund research in search of a cure.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which nerve cell death in the brain and spinal cord leads to muscle atrophy. In a healthy individual, somatic motor neurons transfer signals from the nervous system to skeletal muscles, causing voluntary contractions. For those with ALS, these nerve cells deteriorate or die, denying the patient full ability of movement. As skeletal muscle cells stop receiving signals from motor neurons, muscle tissue begins to wither away from inactivity. ALS is rapidly progressive: It starts with moderate symptoms such as stiffness, weakness, and muscle twitches, but the spread of muscle degeneration eventually costs the patient his mobility. While patients’ mental capacities remain relatively unchanged, they must adapt to the swift loss of physical capabilities, which include walking and speaking clearly. Towards the end of a patient’s life, she typically loses the ability to move entirely, and has difficulty chewing, swallowing, and breathing.

Students at the Yale School of Management participate in the ALS Ice Bucket Challenge. Image courtesy of Insights at SOM.
Students at the Yale School of Management participate in the ALS Ice Bucket Challenge. Image courtesy of Insights at SOM.

There is no cure for ALS. Due to the degeneration of the diaphragm and intercostal muscles that support breathing, the majority of ALS-triggered fatalities are the result of respiratory failure. In most cases, symptoms become fatal in three to five years. The impact of this devastating illness is global. In the United States alone, 12,000 people are currently diagnosed with ALS, making it one of the most common neuromuscular diseases in the world.

The research race to find a treatment for ALS is an ongoing process that, so far, has yielded limited success. Research seems to indicate that neurodegenerative diseases like ALS correlate with disruptions in the equilibrium and functioning of proteins in the body. However, since nearly 90 percent of all ALS cases are sporadic, resulting from no obvious risk factors, it is difficult to identify underlying causes and treatment options for the disease.

Today, scientists continue to investigate the genes and proteins that might be associated with this deterioration of motor neurons. In 2011, researchers at Northwestern University’s Feinberg School of Medicine published findings on a potential common cause for ALS, eliciting an enthusiastic response from the media and scientific community. They had discovered a protein, ubiquilin2, which recycles damaged and misfolded proteins in motor neurons. When a mutation occurs that prevents the proper functioning of ubiquilin2, abnormal proteins accumulate in nerve cells and cause cellular degeneration. This discovery was significant, as it reinforced an existing hypothesis that malfunctioning proteins are involved in the development of ALS.

Unfortunately, the Feinberg discovery did not result in a cure, since experts now estimate that the mutated gene is only present in one percent of inherited ALS cases. The majority of ALS diagnoses are still without an easily discovered commonality, and so the struggle to understand the disease continues.

The development of ALS can be associated with mutations in several different genes, making it difficult to find practical treatments. A team led by Kevin Eggan at Harvard University is working to explore potential similarities between the hundreds of genetic mutations thought to contribute to ALS. Using stem cells to create motor neurons in vitro, the lab compares real ALS neurons with healthy cells. They found that ALS motor neurons are hyper-excitable, firing sporadically and at an increased rate. From this discovery, Eggan’s team theorizes that the independent mutations causing ALS might collectively trigger high rates of neuron activity. These overactive rates of firing make neurons more likely to produce abnormal proteins or to die, potentially leading to the neurological damage of ALS. This research has led to the exploration of retigabine, a drug that appears to reduce the hyper-excitability of motor neurons. Retigabine might therefore be useful in treating ALS. Clinical trials will start this year.

While studies like Eggan’s work to uncover the cause of ALS, other research is advancing our understanding of how symptoms travel through the body. One such study was recently conducted at the University of Florida to investigate the role of deformed proteins. Typically, ALS symptoms begin in a localized region of the central nervous system, where motor neurons begin to deteriorate and the number of inflicted cells subsequently increases. To study this process of motor neuron deterioration, the University of Florida team used an in vivo model to analyze the progression of protein malfunction in mice. Researchers discovered that mice with mutations in SOD1, a gene linked to ALS, developed disease characteristics similar to those observed in ALS patients. Healthy mice, when injected with cell extracts from the spinal cords of SOD1 mutant mice, also began to show the effects of the malfunctioning genotype. The number of misfolded SOD1 proteins in these injected mice increased, indicating that defects in motor neurons are transmissible from neuron to neuron.

Faulty proteins passing between adjacent cells appear to be at fault for the spread of abnormal motor neuron behavior. By studying the transmission of disease symptoms between cells using a genetic mutation known to be involved in ALS, the University of Florida research may offer clues to another possible treatment approach.

The results of these trials are promising for future research, providing several potential pathways towards understanding ALS. However, these studies from the University of Florida and the Harvard Stem Cell Institute are only a small sample of all the research currently investigating this neurodegenerative disease. Understanding ALS and finding new treatments is a daunting, difficult task, but the Ice Bucket Challenge has initiated a new wave of research that supports the hunt for a cure. With increased funding, attention, and dedication from researchers across the nation, there is hope.

Cover Image: Ice Bucket Challenge participants gather to raise awareness for ALS. Image courtesy of NBC News.