- The new compound targets the neurons that initiate voluntary movement
- After 60 days of treatment, the diseased brain cells look like healthy cells
- More research is needed before starting the clinical trial
CHICAGO and EVANSTON — Scientists at Northwestern University have identified the first compound that eliminates the continuous degeneration of diseased upper motor neurons and contributes primarily to ALS (amyotrophic lateral sclerosis), a rapid neurodegenerative disease and mortal that paralyzes its victims.
In addition to ALS, degeneration of upper motor neurons also results in other motor neuron diseases, such as inherited spastic paraplegia (HSP) and primary lateral sclerosis (PLS).
In ALS, nerve cells that initiate movement in the brain (upper motor neurons) and nerve cells that control the muscles in the spinal cord (lower motor neurons) die. The disease results in progressive paralysis and death.
To date, there has been no drug or treatment for the brain component of ALS or any drug for patients with HSP and PLS.
“Although superior motor neurons are responsible for the onset and modulation of movement, and their degeneration is an early occurrence in ALS, so far there has been no treatment option to improve their health,” he said. said lead 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 diseased upper motor neurons.”
The study will be published in Clinical and translational medicine on February 23rd.
Ozdinler collaborated in the research with study author Richard B. Silverman, chemistry professor Patrick G. Ryan / Aon of Northwestern.
The study began after Silverman identified a compound, NU-9, developed in his lab for its ability to reduce protein folding in critical cell lines. The compound is non-toxic and crosses the blood-brain barrier.
The NU-9 compound deals with two of the important factors that cause higher motor neurons to become ill in ALS: protein folding and protein agglomeration inside the cell. Proteins fold in a unique way to function; when folded incorrectly they become toxic to the neuron. Sometimes proteins cluster inside the cell and cause pathology as in the pathology of the TDP-43 protein. This occurs in approximately 90% of all brains of patients with ALS and is one of the most common problems in neurodegeneration.
The research team began investigating whether NU-9 would be able to help repair superior motor neurons that become diseased due to increased protein folding in ALS. The results in mice were positive. The scientists then conducted experiments to reveal how and why diseased upper motor neurons regained health.
The new compound restores neurons for robust health
After administering NU-9, both the mitochondria (the energy producer of the cell) and the endoplasmic reticulum (the protein producer of the cell) began to regain their health and integrity, which improved the health of neurons. The superior motor neurons were more intact, their cell bodies were larger, and the dendrites had no holes. They stopped degenerating so much that diseased neurons became similar to healthy control neurons after 60 days of NU-9 treatment.
Commanders in chief of the movement
“Improving the health of brain neurons is important for ALS and other motor neuron diseases,” Ozdinler said.
The superior motor neurons are the chief commanders of brain movement. They lead the brain’s input to spinal cord targets to initiate voluntary movement. Degeneration of these neurons affects the connection of the brain to the spinal cord and leads to paralysis in patients.
The inferior motor neurons have direct connections to the muscle, contracting the muscle to execute movement. Thus, the activity of the lower motor neurons is controlled in part by the higher motor neurons.
Ozdinler and colleagues will now complete more detailed toxicology and pharmacokinetic studies before initiating a phase 1 clinical trial.
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Ozdinler and Silverman are members of Northwestern’s Chemistry of Life Processes Institute.
Other Northwestern study authors include Bar ?? Young, Mukesh Gautam, Öge Gözütok, Ina Dervishi, Santana Sanchez, Gashaw Goshu, Nuran Koçak and Edward Xie.
The study was funded by grant R01 AG061708 from the National Institute on Aging of the National Institutes of Health, NUCATS, Northwestern University, Les Turner ALS Foundation and the ALSA TREAT ALS Award.
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