ALS, or amyotrophic lateral sclerosis, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. ALS, also known as Lou Gherig’s disease, destroys the nerve cells called motor neurons that control voluntary muscle movement.  In ALS, these cells die off, causing the muscle tissues to waste away.

ALS affects as many as 30,000 in the United States, with 5,000 new cases diagnosed each year. Unfortunately, there is no cure or treatment that halts or reverses the progression of the disease. However, there are FDA-approved medications that help modestly slow the progression of ALS, and several promising clinical trials are being conducted to combat the devastating disease. A new study is also showing promising news. Using a mouse model, researchers from Northwestern University say they have identified the first compound that eliminates the ongoing degeneration of upper motor neurons that become diseased and are a key contributor to ALS.

Their findings, ” Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP‐43 pathology,” was published in Clinical and Translational Medicine.

Degeneration of upper motor neurons (UMNs) is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and ALS. Improving the health of degenerating UMNs will have broad implications both within the context of injury and neurodegeneration.

“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,” explained senior author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine. “We have identified the first compound that improves the health of upper motor neurons that become diseased.”

Although motor neuron diseases mostly develop because motor neurons degenerate, there has never been a study that investigates the health and improvement of diseased UMNs at a cellular level.

Ozdinler collaborated on the research with study author Richard B. Silverman, the Patrick G. Ryan/Aon professor of chemistry at Northwestern. Ozdinler and Silverman initiated the study after Silverman identified a compound, NU-9, developed in his lab for its ability to reduce protein misfolding in critical cell lines.

The misfolding and aggregation of proteins such as Cu-Zn superoxide dismutase (SOD1) and TAR-DNA-binding protein of 43 kDa (TDP-43) are believed to be key features of ALS. The NU-9 compound is able to cross the blood-brain barrier and is nontoxic.

The researchers sought to determine whether NU-9 would be able to help repair UMNs that become diseased due to increased protein misfolding in ALS. The results in mice were positive. The researchers then performed experiments to reveal how and why the diseased upper motor neurons regained their health.

After NU-9 was administered, the mitochondria and the endoplasmic reticulum began to regain their health and integrity. The researchers observed the UMNs were more intact, and stopped degenerating. The diseased neurons became similar to healthy control neurons after 60 days of NU-9 treatment.

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

Further studies are needed before moving into a clinical trial, but the new findings offer hope for ALS treatment, and may pave the way for other studies and treatments of neurodegenerative diseases to arise.

“Our findings mark the identification of the first compound that improves the health of diseased UMNs, and lay the foundation for future mechanism‐focused and cell‐based drug discovery studies,” concluded the researchers.

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