Study Reveals New Insights Into SOD1 Mutations and ALS
A study led by researchers at the National Institute of Neurological Disorders and Stroke (NINDS) recently published in the journal Neuron revealed new insights into why mutations in the SOD1 gene lead to the development of amyotrophic lateral sclerosis (ALS). The study is entitled “Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice”.
ALS is the most common neurodegenerative disease that affects the motor neuron system. The disorder is characterized by the gradual degeneration and atrophy of motor neurons in the brain and spinal cord. ALS patients may become totally paralyzed and the majority die due to respiratory failure within two to five years after diagnosis. It is estimated that there are 30,000 ALS patients in the U.S., and that approximately 5,600 individuals are diagnosed every year. Currently, there is no cure for ALS.
It is estimated that 5 to 10% of all ALS cases are due to an inherited genetic mutation, often in the superoxide dismutase 1 (SOD1) gene. This gene encodes a key protein important for the detoxification of motor neurons. SOD1 is found in the neuron’s mitochondria, small organelles where cellular energy is produced.
“About 90 percent of the energy in the brain is generated by mitochondria,” said the study’s senior author Dr. Zu-Hang Sheng in a news release. “If the mitochondria aren’t healthy, they produce energy less efficiently; they can also release harmful chemicals called reactive oxygen species that cause cell death. As a consequence, mitochondrial damage can cause neurodegeneration.”
In the study, researchers used ALS mice models with mutations in the SOD1 gene. “Mutant SOD1 mice are the best-studied models we have for ALS,” explained Dr. Sheng. “The effects are very similar to the symptoms found in human patients.”
The team found that in these animals there was an accumulation of damaged mitochondria in the motor nerve fibers, even in early stages of the disease before any manifestation of symptoms. SOD1 was found to interfere with a key protein called snapin that makes the bridge between endosomes, where the damaged mitochondria and deleterious chemicals are collected, and the dynein motor protein that transports the endosomes to structures called lysosomes where the degradation of the defective elements occurs.
“Snapin functions as an adaptor to link the dynein protein to the endosome for transport,” explained Dr. Sheng. “If you block snapin function, the endosome will be stuck and the lysosomes will lose their ability to destroy damaged mitochondria.”
Researchers showed that increasing snapin levels in neurons during the early, asymptomatic stage of ALS could reduce the accumulation of defective mitochondria, which ultimately increased the survival rate of motor neurons and slightly increased the animals’ lifespans. This strategy also slowed down the loss of motor coordination in the animals typical of ALS due to the death of motor neurons.
“We provide a new mechanistic link that explains why mutant SOD1 impairs endosome transport,” concluded Dr. Sheng. “This can provide a cellular target for future development of early therapeutic interventions when motor neurons may still be salvageable.”
This study was the first one in the ALS research field to analyze endosome transport in cultured motor neurons from adult ALS mice models instead of mouse embryos. The authors reasoned that adult motor neurons would be a better model for the study of ALS as disease symptoms usually develop during adulthood. “By using adult motor neurons from the mice models, we found this transport defect,” added Dr. Sheng. “This model may be useful not only for studying ALS but also other adult-onset diseases that cause neurodegeneration.”