ALS Neuron Damage Reversed With New Compound

Summary: NU-9, a novel, non-toxic compound, targets upper motor neurons and reverses damage associated with ALS within 60 days of treatment.

Source: Northwestern University

Northwestern University scientists have identified the first compound that eliminates the ongoing degeneration of upper motor neurons that become diseased and are a key contributor to ALS (amyotrophic lateral sclerosis), a swift and fatal neurodegenerative disease that paralyzes its victims.

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

In ALS, movement-initiating nerve cells in the brain (upper motor neurons) and muscle-controlling nerve cells in the spinal cord (lower motor neurons) die. The disease results in rapidly progressing paralysis and death.

So far, there has been no drug or treatment for the brain component of ALS, and no drug for HSP and PLS patients.

“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,” said 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.”

The study will be published in Clinical and Translational Medicine on February 23.

Ozdinler collaborated on the research with study author Richard B. Silverman, the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern.

The study was initiated after Silverman identified a compound, NU-9, developed in his lab for its ability to reduce protein misfolding in critical cell lines. The compound is not toxic and crosses the blood brain barrier.

The NU-9 compound addresses two of the important factors that cause upper motor neurons to become diseased in ALS: protein misfolding and protein clumping inside the cell. Proteins fold in a unique way to function; when they misfold they become toxic to the neuron. Sometimes proteins aggregate inside the cell and cause pathology as in the TDP-43 protein pathology. This happens in about 90% of all ALS patient brains and is one of the most common problems in neurodegeneration.

In addition to ALS, upper motor neuron degeneration also results in other motor neuron diseases, such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Image is in the public domain

The research team began to investigate whether NU-9 would be able to help repair upper motor neurons that become diseased due to increased protein misfolding in ALS. The results in mice were positive. Scientists next performed experiments to reveal how and why the diseased upper motor neurons regained their health.

New compound restores neurons to robust health

After administering NU-9, both the mitochondria (the cell’s energy producer) and the endoplasmic reticulum (the cell’s protein producer) began to regain their health and integrity resulting in improved neuron health. The upper motor neurons were more intact, their cell bodies were larger and the dendrites were not riddled with holes. They stopped degenerating so much that the diseased neurons became similar to healthy control neurons after 60 days of NU-9 treatment.

Commanders-in-chief of movement

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

Upper motor neurons are the brain’s commanders-in-chief of movement. They carry the brain’s input to spinal cord targets to initiate voluntary movement. The degeneration of these neurons impairs the connection from the brain to the spinal cord and leads to paralysis in patients.

Lower motor neurons have direct connections with the muscle, contracting muscle to execute movement. Thus, the lower motor neuron activity is in part controlled by the upper motor neurons.

Ozdinler and colleagues will now complete more detailed toxicology and pharmacokinetic studies prior to initiating a Phase 1 clinical trial.

Ozdinler and Silverman are members of the Chemistry of Life Processes Institute at Northwestern.

Other Northwestern study authors include Bar Genç, Mukesh Gautam, Öge Gözütok, Ina Dervishi, Santana Sanchez, Gashaw Goshu, Nuran Koçak and Edward Xie.

Funding: The study has been 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.

About this ALS research news

Source: Northwestern University
Contact: Marla Paul – Northwestern University
Image: The image is in the public domain

Original Research: Open access.
Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP‐43 pathology” by Richard B. Silverman et al. Clinical and Translational Medicine


Abstract

Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP‐43 pathology

Background

Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies.

Methods

Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP‐43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU‐9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses.

Results

Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU‐9 has drug‐like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU‐9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP‐43 pathology, two distinct and important overarching causes of motor neuron degeneration.

Conclusions

Mechanism‐focused and cell‐based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU‐9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.

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