Supplementing Spinal Cord Protein Delays Muscle Atrophy in ALS

Supplementing a protein found in the spinal cord could potentially prevent symptoms associated with amyloid lateral sclerosis (ALS), or Lou Gehrig’s disease, according to a new study conducted by investigators at Case Western Reserve University School of Medicine in Cleveland, Ohio.

Using mouse models of the disease, the investigators found that increased levels of the protein mitofusion 2 (Mfn2) prevented nerve degradation, muscle atrophy, and paralysis. As the protein is often depleted in those with the disease, the new findings indicate that supplementing the protein could serve as a potential therapeutic approach for those with ALS.

“We found a way to alleviate age and ALS-related muscular atrophy in our mouse models,” said Xinglong Wang, PhD, associate professor of pathology at Case Western Reserve University School of Medicine, in a recent statement. “Amazingly, we could delay ALS symptom onset by 67 days.”

For their study, published in Cell Metabolism, investigators tested the most widely used ALS model by genetically engineering the diseased mice to have increased levels of the Mfn2 protein in the nerve cells that extend from the spinal cord and connect to muscle fibers.

The investigators found that mice with high Mfn2 levels in the modified nerves were at a healthy weight, and did not have any of the muscle atrophy, gait abnormalities, or reduced grip strength which the mice in the control groups had developed. Additionally, even mice that experienced heavy sciatic nerve damage were found to benefit from the increased levels of Mfn2.

After studying nerve cells that were collected from the mice, Dr Wang and his team unveiled just how Mfn2 provided protective effects. Specifically, the team found that Mfn2 coexists with mitochondria. Their research showed that mitochondria travel along axons to deliver nutrients to a specific point—where nerve cells and muscle fibers meet—which preserves synapses between the nerve and muscle cells, preventing muscle atrophy.

“We found mitochondria function as miniature ‘trucks’ to transport protein along axons to prevent synaptic degeneration,” explained Dr Wang. “Upregulation of Mfn2 specifically in nerve cells is sufficient to abolish skeletal muscle loss in ALS and aged mice, despite ALS-causing protein being found in all organs and tissues.”

Although they are not typically known for cellular transport functions, the mitochondria was found to use Mfn2 on their surfaces to carry calpstatin, a nutrient that hinders harmful enzymes that degrade nerves and muscle fibers. By carrying calpstatin, they are able to prevent the enzymes from destroying synapse connections. Mitochondria are unable to carry calpstatin without Mfn2.

"We have for the first time found that in addition to acting as the power stations of cells, mitochondria are directly involved in the protein transport along axons to regulate synaptic degeneration," Dr Wang told Rare Disease Report ^®. "Thus, our study reveals a novel molecular mechanism for synaptic maintenance via mitochondria."

Dr Wang hopes the team’s research can be used to inform the development of novel and more effective therapies for ALS as well as other neurodegenerative diseases.

“The upregulation of mitofusin2 only in neurons is sufficient to remarkably abolish age—and ALS—associated neuromuscular synapse loss and skeletal muscle atrophy, and amazingly delay the symptom onset of the most widely used ALS mouse model by more than 2 months, Dr Wang told Rare Disease Report ^®. "This suggests that mitofusin2 may be a novel common therapeutic target for a wide range of diseases associated with synaptic or neuromuscular synaptic abnormalities, including but not limited to ALS, Spinal muscular atrophy (SMA) and even Alzheimer's disease."

Dr Wang and his team are in the process of studying the protective role of Mfn2 in other disease models with neuromuscular or brain synaptic loss. "We are also trying to screen small molecules specifically boosting the function of mitofusin2 in regulating protein transport," he said.