Monday , March 8 2021

Damage to ALS neurons was reversed by the new compound

  • The new compound targets neurons that trigger voluntary movement
  • After 60 days of treatment, diseased brain cells look like healthy cells
  • More research is needed before starting a clinical trial

CHICAGO and EVANSTON — Scientists at Northwestern University have identified the first compound that eliminates the ongoing degeneration of upper motor neurons that become ill and are a key factor in ALS (amyotrophic lateral sclerosis), a rapid and fatal neurodegenerative disease that paralyzes its victims.

In addition to ALS, upper motor neuron degeneration results in other motor neurone diseases, such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS).

In ALS, nerve cells that drive 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 rapidly progressing paralysis and death.

So far, there have been no drugs or treatments for the brain component of ALS, as well as drugs for patients with HSP and PLS.

“Although upper motor neurons are responsible for initiating and modulating movement, and their degeneration is an early event in ALS, so far there has been no treatment option to improve their health,” said senior author Hande Ozdinler, an associate professor of neurology at the School of Medicine. Northwestern University Feinberg. “We have identified the first compound that improves the health of upper motor neurons that become diseased.”

The study will be published in Clinical and translational medicine February 23.

Ozdinler collaborated on the study with study author Richard B. Silverman, Patrick G. Ryan / Aon is a professor of chemistry in the Northwest.

The study began after Silverman identified a compound, NU-9, developed in his laboratory because of its ability to reduce the misfolding of proteins in critical cell lines. The compound is non-toxic and crosses the blood-brain barrier.

Compound NU-9 deals with two important factors that cause the upper motor neurons to suffer from ALS: incorrect assembly of proteins and accumulation of proteins in the cell. Proteins fold in a unique way; when mistaken they become toxic to the neuron. Sometimes proteins aggregate within the cell and cause pathology as in TDP-43. This occurs in about 90% of all brains of patients with ALS and is one of the most common problems in neurodegeneration.

The research team has begun researching whether NU-9 will be able to help repair upper motor neurons that become diseased due to increased protein misalignment in ALS. The results on the mice were positive. The scientists then performed experiments to find out how and why the diseased upper motor neurons regained their health.

The new compound restores neurons to good health

After the application of NU-9, both mitochondria (cellular energy producer) and endoplasmic reticulum (cellular protein producer) begin to regain their health and integrity, which results in improved neuronal health. The upper motor neurons were more intact, their cellular bodies were larger and the dendrites were not filled with holes. They stopped degenerating so much that diseased neurons became similar to healthy control neurons after 60 days of NU-9 treatment.

Supreme commanders of the movement

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

The upper motor neurons are the main commanders of brain movement. They carry the brain that enters the targets of the spinal cord in order to initiate voluntary movement. Degeneration of these neurons disrupts the connection from the brain to the spinal cord and leads to paralysis in the patient.

The lower motor neurons have direct connections with the muscle, contracting the muscle to perform the movement. Thus, the activity of the lower motor neuron is partially controlled by the upper motor neurons.

Ozdinler and colleagues will now complete more detailed toxicological and pharmacokinetic studies before beginning a phase 1 clinical trial.


Ozdinler and Silverman are members of the Institute for the Chemistry of Life Processes in the Northwest.

Other authors of the Northwest study include Bar ?? Young, Mukesh Gautam, Oge Gozutok, Ina Dervishi, Santana Sanchez, Gashav Goshu, Nuran Kocak and Edward Xie.

The study was funded by grant R01 AG061708 of 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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