Mutant Gene Causes Some ALS Symptoms through Mitochondrial Damage

Mutant Gene Causes Some ALS Symptoms through Mitochondrial Damage

Three Packard-funded investigators show how a gene linked to ALS can cause motor neuron damage.

Giovanni Manfredi

A team of researchers from Weill Medical College of Cornell University and Emory University, including Giovanni Manfredi, Jordi Magrané and Jonathan Glass, three Packard Center scientists, published a new study that shows how a gene linked to amyotrophic lateral sclerosis (ALS) can cause motor neuron damage. The study, published on November 2 in the Journal of Neuroscience, showed that a mutant form of the SOD1 gene leaves motor neurons unable to obtain adequate energy when working hard. This, the scientists say, ultimately damages the motor neuron.

Previous studies had identified abnormalities in the motor neuron mitochondria (the cell’s power plants) in familial ALS patients who carried a mutant version of SOD1. What researchers didn’t know was whether the mitochondrial changes actually caused the motor neuron damage or whether these pathological changes were a result of the damage. “We didn’t know if mitochondrial dysfunction was the chicken or the egg,” said Manfredi, the study’s senior author and a neuroscientist at Weill Cornell Medical School. “We wanted to know whether there was direct damage caused by SOD1 localizing in the mitochondria.”

To test the relationship between mutant SOD1 and mitochondrial damage, the researchers used transgenic mice that carried a common form of the mutant SOD1 seen in familial ALS patients. They also attached a small tag that would confine the mutant SOD1 to the mitochondria, which ensures that any mitochondrial changes were due to the presence of the mutant protein. The scientists compared these mice to mice with wild-type SOD1 confined to the mitochondria, mice whose mutant SOD1 wasn’t confined to the mitochondria and normal, healthy mice.

The mice with the mutant SOD1 in the mitochondria showed some of the physical signs and symptoms of ALS, such as weight loss, motor difficulties, motor neuron loss, and muscle atrophy. As well, these mice showed physical and biochemical changes to their motor neuron mitochondria. Although the mitochondria performed normally when the motor neurons were at rest, they weren’t able to produce enough energy when the cells had to work hard. The researchers hypothesize that the aggregates of mutant SOD1 cause the mitochondrial damage by interfering with the process of enzyme formation or by using up too much copper, leaving other enzymes unable to function properly.

Still, the researchers found significant differences between the mice whose mutant SOD1 was confined to the mitochondria and those whose mutant SOD1 was free in the cell. The mitochondrial mutants had later disease onset (8 months of age vs. 3 months in regular SOD1 mutant mice) and no significant loss of lifespan compared to control mice. As well, the mitochondrial mutants didn’t show any loss of connection between their motor neurons and muscle cells.

Thus, Manfredi said, the presence of mutant SOD1 in the mitochondria causes some, but not all, of the pathogenic changes associated with ALS. “Mutant SOD1 in the mitochondria causes dysfunction, and it causes degeneration of neurons. Despite this, it doesn’t seem to cause the full-fledged, complete pathological picture that is the hallmark of ALS,” Manfredi said.