Fighting Disease Targeting Children

Harvard Stem Cell Institute (HSCI) scientists analyzing spinal muscular atrophy (SMA) have discovered “surprising similarities” between this childhood disorder that attacks motor neurons and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The findings have been published online by the journal Cell Stem Cell and reported in Bioscience Technology. 
 
The research team led by HSCI principal faculty member Lee Rubin uncovered molecular changes that explain, at least in part, why motor neurons, rather than others, are affected by the illness. Unlike ALS and other neurodegenerative diseases, which tend to manifest later in life, SMA strikes infants. Also unlike ALS, SMA is a genetic disorder that causes a range of outcomes, with the milder form leaving some children confined to wheelchairs, and the more severe form causing paralysis and death before the second birthday.
 
While not as well-known as ALS, SMA is “the most frequent fatal genetic disease of young children,” said Rubin, a professor in Harvard’s Department of Stem Cell and Regenerative Biology (HSCRB) in the Harvard Gazette. The article said that one in 50 people is a carrier of SMA, and one in 5,000 children is born with the disease.
 
Researchers are determining the mechanisms of SMA. According to Rubin, “It has never been clear why motor neurons, which relay signals from the brain to the muscles via the spinal column, die selectively. It is clear motor neurons die well before other kinds of cells, even other kinds of spinal-cord neurons, and the mystery has been trying to understand that.”
 
A research team of HSCI investigators at the Broad Institute of Harvard and MIT and HSCRB collaborated with the SMA Foundation’s Pediatric Neuromuscular Clinical Research Network and Columbia University College of Physicians and Surgeons to make neurons from donors with SMA of varying degrees of severity.
 
The researchers first determined that the neurons in a dish behaved similarly to the way neurons would behave in an SMA patient. Motor neurons died before other types of neurons, and motor neurons from patients with severe SMA died very quickly in comparison to others. Using a method of intracellular cell labeling developed at HSCI, the researchers separated motor neurons from other types of neurons in the dish, carried out an RNA sequencing analysis and compared SMA motor neurons to those from healthy individuals.
 
While healthy cells maintain an appropriate quantity of protein made by genes that are turned on within a given cell, neural cells targeted by late-onset neurodegenerative diseases lose their ability to maintain that balance, and the clutter stresses the cell. If unresolved, the cells shut down and die. When a number of cells die, patients start to experience the effects of their disease.
 
SMA works in the opposite way: there is too little of a specific protein, called survival of motor neuron (SMN), because the gene that codes that protein is broken. The reduction in this protein affects the cells’ ability to process other proteins normally, leading to a motor neuron stress response.
 
When the team shut off the stress response in the SMA-affected cells, they could keep the motor neuron cells from dying. While the two diseases have different origins, they both involve a stress response in motor neurons specifically and could eventually be treated by one drug.