ALS, also known as Lou Gehrig's disease, is a devastating neurological disorder that gradually destroys the nerve cells controlling voluntary movement. As motor neurons die, patients progressively lose the ability to walk, speak, swallow, and eventually breathe. Although mitochondrial dysfunction has long been linked to ALS, scientists have struggled to determine whether it is a cause of the disease or simply a consequence of dying neurons.
To investigate this question, the researchers engineered mice lacking ROMO1 specifically in cholinergic neurons, a group of nerve cells responsible for controlling muscle movement. As the mice aged, they developed worsening muscle weakness and movement problems that closely resembled ALS. They also showed motor neuron loss, degeneration of nerve fibers, disruption of the connections between nerves and muscles, reduced levels of the neurotransmitter acetylcholine, and severe muscle wasting.
One of the study's most striking findings was that damage to mitochondria occurred well before the animals showed any signs of muscle weakness. Using high-resolution electron microscopy, the researchers found that mitochondria gradually lost their normal internal architecture, with their energy-producing membrane structures becoming swollen, distorted, and eventually collapsing. Because these mitochondrial abnormalities appeared before motor neuron degeneration, the findings suggest that mitochondrial damage is an early event that may actively drive disease progression.
The team also found that ROMO1 levels were markedly reduced in a widely used mouse model of ALS as well as in motor neurons generated from patients with ALS, suggesting that ROMO1 deficiency may be associated with the disease in humans.
"ROMO1 is essential for maintaining healthy mitochondria in motor neurons," said Dr. Xianhua Wang , senior author of the study. "Our findings provide evidence that mitochondrial damage is not simply a byproduct of ALS, but may be an early trigger of motor neuron degeneration."
While additional research is needed to determine whether therapies targeting ROMO1 could benefit patients, the discovery identifies ROMO1 as a promising new target for understanding ALS and developing future treatments. The work also highlights the importance of maintaining mitochondrial health to preserve motor neuron function and combat neurodegenerative diseases.
Science Bulletin