ALS brain cell damage reversed by new compound in breakthrough discovery

EVANSTON, Ill. — For patients with amyotrophic lateral sclerosis (ALS), the diagnosis can be like receiving a death sentence. For over a century, there has been no cure for the neurological condition which attacks the motor neurons and leads to paralysis. Now, researchers from Northwestern University have discovered a compound they say can reverse the damage to the brain cells attacked by ALS and similar conditions.

ALS, also called Lou Gehrig’s disease or motor neuron disease, is a degenerative disease which attacks the brain and muscles. This incurable condition slowly breaks down the links between the brain’s nerve cells (upper motor neurons) and the spinal cord’s muscle-controlling cells (lower motor neurons). Most patients also lose the ability to speak without mechanical assistance and die within two to five years of their diagnosis.

The new study pinpointed the first compound ever discovered which can stop the degeneration of upper motor neurons. Along with ALS, diseased upper motor neurons can also cause conditions like hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) to develop. There is currently no drug which can stop the brain degeneration tied to any of these conditions.

“Even though the upper motor neurons are responsible for the initiation and modulation of movement, and their degeneration is an early event in ALS, so far there has been no treatment option to improve their health,” explains senior author Hande Ozdinler, associate professor of neurology at Northwestern’s Feinberg School of Medicine, in a university release. “We have identified the first compound that improves the health of upper motor neurons that become diseased.”

NU-9 may help cure ALS

Ozdinler and study author Richard Silverman identified the compound NU-9 during lab studies on diseased brain cells. This compound tackles two major factors which causes upper motor neurons to deteriorate during ALS; those being protein misfolding and protein clumping in the cells.

ALS compound brain cells
Neurons before and after treatment with NU-9. (Credit: Chemistry of Life Processes Institute at Northwestern)

Researchers say that sometimes the proteins in the human body will cluster inside cells and cause diseases to develop, such as the TDP-43 protein pathology. This particular protein malfunction takes place in about 90 percent of all ALS patient brains. It’s one of the most common problems scientists see with neurodegeneration.

In tests on mice, NU-9 repaired upper motor neurons damaged due to misfolding proteins. After just 60 days of treatment, diseased brain cells began to look and function like healthy control neurons again. Along with regaining their function, cells treated with NU-9 also became larger and the nerve branches coming from them had fewer holes.

“I am very excited to find out if our hypothesis that stabilizing upper motor neurons in mice will translate to humans and NU-9 will provide hope for those inflicted with currently untreatable upper motor neuron diseases,” Silverman adds.

Both the mitochondria (the cell’s energy producer) and the endoplasmic reticulum (the cell’s protein producer) also regained their health and integrity during the study.

Restoring the commanders of movement to power

“Improving the health of brain neurons is important for ALS and other motor neuron diseases,” Ozdinler says.

The team adds that upper motor neurons act like the “commanders-in-chief” of body movement. They carry brain signals to the spinal cord which triggers each person’s voluntary movements. When these paths degenerate during ALS, the connections between the brain and body break down. Without the ability to get signals through, patients slip into paralysis.

The lower motor neurons connect directly to the body’s muscles, signaling them to contract to trigger movement. Therefore, lower motor neuron activity is also controlled by the upper motor neurons treated by NU-9.

Researchers also point out that the breakthrough compound is not toxic and can cross the blood brain barrier. This makes it capable of reaching diseased neurons in the brains of human patients.

The Northwestern team is now planning to finish a more detailed toxicology and pharmacokinetic study before starting a Phase 1 clinical trial of NU-9.

The study appears in the journal Clinical and Translational Medicine.