Summary: NU-9, a new non-toxic compound, targets upper motor neurons and reverses cellular damage associated with ALS within 60 days of treatment.
Source: Northwestern University
Researchers at Northwestern University have discovered the first compound that halts and reverses degeneration of upper motor neurons — a critical cell type whose decline drives amyotrophic lateral sclerosis (ALS) and contributes to other motor neuron disorders.
Degeneration of upper motor neurons also underlies related conditions such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS).
In ALS, the disease kills upper motor neurons in the brain that initiate movement, as well as lower motor neurons in the spinal cord that directly control muscles. This dual loss produces rapidly progressive paralysis and ultimately leads to death.
To date, no treatment has been available that specifically protects or restores the brain’s upper motor neurons, and patients with HSP and PLS likewise lack targeted therapies.
“Although degeneration of upper motor neurons is an early and central event in ALS, there have been no options 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 restores health to diseased upper motor neurons.”
The study is scheduled for publication in Clinical and Translational Medicine on February 23.
Ozdinler collaborated with Richard B. Silverman, the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern, on the research team.
The investigation began when Silverman’s lab identified NU-9, a compound that reduces harmful protein misfolding in key cell models. NU-9 is not toxic in tested models and is able to cross the blood–brain barrier, making it a promising candidate for central nervous system disease.
NU-9 targets two central problems that drive upper motor neuron disease in ALS: protein misfolding and intracellular protein aggregation. Proper protein folding is essential for normal function, while misfolded proteins become toxic and can accumulate into clumps that disrupt cell biology. One common pathological signature in roughly 90% of ALS brains is abnormal TDP-43 protein accumulation, a form of protein aggregation linked to neurodegeneration.
The team tested whether NU-9 could restore health to upper motor neurons impaired by increased protein misfolding in ALS models. Results in mice were encouraging, and further experiments sought to define how NU-9 reverses neuronal damage at the cellular and ultrastructural levels.
NU-9 restores cellular integrity and halts degeneration
Following NU-9 treatment, researchers observed marked recovery of two vital organelles: mitochondria, the cell’s energy producers, and the endoplasmic reticulum (ER), the site of protein synthesis and folding. As mitochondrial and ER structure and function improved, so did overall neuron health. Diseased upper motor neurons developed larger, healthier cell bodies and dendrites free of the holes and fragmentation seen in degenerating cells. After 60 days of NU-9 treatment, affected neurons closely resembled healthy control neurons, indicating that the compound not only slowed degeneration but actually reversed structural damage.
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 serve as the brain’s commanders of voluntary movement, sending signals to spinal cord targets to initiate and modulate motion. Their degeneration disrupts brain-to-spinal cord communication and contributes directly to paralysis.
Lower motor neurons connect directly to muscles and execute the movement commands. Because lower motor neuron function depends in part on input from upper motor neurons, protecting the brain’s neurons is critical for preserving the entire motor pathway.
Next steps for the team include completing detailed toxicology and pharmacokinetic studies required before launching a Phase 1 clinical trial.
Ozdinler and Silverman are affiliated with Northwestern’s Chemistry of Life Processes Institute.
Additional Northwestern contributors to the study include Bar Genç, Mukesh Gautam, Öge Gözütok, Ina Dervishi, Santana Sanchez, Gashaw Goshu, Nuran Koçak and Edward Xie.
Funding: The research received support from grant R01 AG061708 from the National Institute on Aging (National Institutes of Health), NUCATS, Northwestern University, the 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 central to motor circuitry, and their loss is a defining feature of disorders such as HSP, PLS, and ALS. Until now, there have been no preclinical assays that directly measure UMN responses to candidate compounds, and the cellular basis for UMN vulnerability remains incompletely understood. The absence of compounds that improve the health of diseased UMNs has been a major barrier to developing effective therapies.
Methods
The investigators used novel UMN reporter models in which diseased UMNs — impaired by misfolded superoxide dismutase (mSOD1) toxicity or TDP‑43 pathology — express eGFP, enabling direct visualization of cellular responses to treatment. Electron microscopy provided detailed views of ER and mitochondrial damage. NU-9, originally identified for its ability to reduce mSOD1 toxicity, was administered and its effects on UMN structure and stability were assessed through cellular and ultrastructural analyses.
Results
Mitochondrial and ER defects were consistently observed in diseased UMNs across species. NU-9 demonstrates favorable drug-like pharmacokinetics, lacks toxicity in preclinical testing, and penetrates the blood–brain barrier. Treatment with NU-9 improved mitochondrial and ER structural integrity, lowered mSOD1 levels, stabilized degrading UMN apical dendrites, enhanced motor performance in behavioral tests such as the hanging wire assay, and stopped ongoing degeneration of UMNs affected by both mSOD1 toxicity and TDP‑43 pathology — two major drivers of motor neuron disease.
Conclusions
A mechanism-focused, cell-based drug discovery approach allowed the team to address critical cellular defects responsible for UMN loss and to identify NU-9 as the first compound that improves the health of diseased upper motor neurons. These findings support further preclinical development of NU-9 and lay groundwork for potential clinical testing in ALS, HSP, PLS, and related conditions.