Researchers at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke have learned how a mutation in the gene for superoxide dismutase 1, which causes ALS (aka Lou Gehrig’s disease), leads cells to accumulate damaged materials. The study, published in the journal Neuron, suggests a potential target for treating this familial form of ALS.
ALS can be caused by inherited mutations in the gene that codes for SOD1, an important enzyme located in the neuron’s mitochondria, according to a news release. This mutation causes the death of motor neurons that control the patient’s muscles, resulting in progressive paralysis.
“About 90% of the energy in the brain is generated by mitochondria,” Zu-Hang Sheng, PhD, an NINDS scientist and the study’s senior author, said in the 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 healthy neurons, storage containers called late endosomes collect damaged mitochondria and destructive chemicals. A motor protein, dynein, then transports the endosomes to lysosomes, which use the chemicals to break down the endosomes. Sheng’s team discovered mutant SOD1 interferes with snapin, a critical molecule that hooks the endosome to the dynein motor protein.
“Snapin functions as an adaptor to link the dynein protein to the endosome for transport,” Sheng said in the release. “If you block snapin function, the endosome will be stuck and the lysosomes will lose their ability to destroy damaged mitochondria.”
Sheng and his colleagues conducted their experiments in mice engineered to have an ALS mutation in their SOD1 genes. Using light and electron microscopes, the study’s co-first author, Yuxiang Xie, PhD, observed a buildup of damaged mitochondria in the mutant animals’ motor nerve fibers. This accumulation was present even in early stages of the disease before overt symptoms emerged.
Snapin attaches dynein to the endosomes via a part of the protein called the dynein intermediate chain. In spinal cord motor neurons from the affected mice, Sheng’s team found the altered SOD1 binds to the DIC and prevents snapin from doing so. Increasing the amount of snapin in these neurons during the early, asymptomatic stage of the disease corrected the problem and reduced the buildup of defective mitochondria. This helped the motor neurons to survive longer and slightly increased the animals’ lifespans. It also slowed down the loss of motor coordination, which worsens in animals with the SOD1 mutation as motor neurons die.
“We provide a new mechanistic link that explains why mutant SOD1 impairs endosome transport,” Sheng said. “This can provide a cellular target for future development of early therapeutic interventions when motor neurons may still be salvageable.”
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