ALS is driven by a domino‑like chain reaction that begins in nerve cells

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ALS is driven by a domino-like chain reaction that begins in nerve cells

Study links TDP-43 pathology to inflammation, disease progression and survival across ALS subtypes

• Study used cutting-edge techniques to analyze blood, spinal cord samples from hundreds of patients
• Immune signatures differ by ALS type (genetic or non-genetic), disease stage, speed of progression
• Level of inflammation correlates with the rate of disease progression: 'the less inflammation an ALS patient has in their spinal cord, the longer they will survive'

CHICAGO --- Patients with ALS, or Lou Gehrig's disease, live an average of only three years after symptoms begin, though some can survive closer to 10 years. What drives these differences in survival has remained a mystery.

A new Northwestern Medicine study provides new insight, identifying evidence that ALS unfolds through a domino-like sequence of events that begins with an early breakdown inside motor neurons and is followed by a damaging inflammatory response. The findings help explain why the disease worsens over time, why some patients progress faster than others and how future treatments could be more personalized.

The study will be published May 14 in Nature Neuroscience*.

The domino effect

"This study reveals that ALS is not a single event but a domino-like cascade that begins inside motor neurons with TDP-43 pathology and is then amplified by a damaging immune response in the bloodstream and spinal cord," said co-corresponding author David Gate, director of the Abrams Research Center on Neurogenomics at Northwestern University Feinberg School of Medicine.

The study found immune cells converge at sites of motor neuron loss and TDP-43 pathology - a hallmark of ALS - with distinct inflammatory patterns depending on the type of ALS (genetic or non-genetic, the most common form) and how quickly the disease progresses.

"The intensity of spinal cord inflammation doesn't determine when someone develops ALS - it determines how fast the disease progresses and how long they survive," said co-corresponding author Evangelos Kiskinis, associate professor of neurology and neuroscience at Feinberg. "If we can target these immune signatures therapeutically, we can slow down the rate of disease progression."

Using cutting-edge techniques, the scientists analyzed blood and spinal cord samples from almost 300 patients - living and deceased - with both non-genetic and genetic (caused by changes in the C9orf72 gene) forms of ALS, as well as controls.

"We found the immune cells we detected in the blood of people living with ALS were inflamed, and we found the genes that mediate their inflammatory response in the spinal cord at the site of motor neurons," Gate said. "These inflamed immune cells were associated with ALS pathology, giving some credence to our theory that the immune system is detrimental. It's responding to pathology, and it's causing the disease to be worse."

The findings suggest if treatments can target these immune signatures, they can slow down the rate of disease progression, and that future therapeutics may need to be tailored to specific ALS subtypes and disease stages to be most effective, the authors said.

Sophisticated scientific techniques

"For ALS, this work is highly novel," said Gate, also an assistant professor of neurology at Feinberg. "This is the first in-depth molecular assessment of how the immune system behaves across different forms of ALS, using technologies that allow us to pinpoint which immune genes are active in patient tissues, and where."

The scientists used single-cell RNA sequencing technology to analyze blood samples from 40 living ALS patients and used spatial transcriptomics, a technique that allows them to pinpoint the specific spatial location of gene activity inside a tissue sample, to analyze spinal cord tissue from 18 deceased participants. They compared patients with non-genetic ALS to those with the genetic form, which allowed the scientists to see how immune activity differs across ALS types and disease stages. To further analyze inflammatory responses within the central nervous system of ALS patients, the scientists examined RNA from postmortem samples of 237 ALS patients.

Patients whose disease advanced quickly showed heightened activity in certain immune genes, while those with the genetic form had a different array of altered immune genes. In the spinal cord, these activated immune cells gathered directly at the locations of motor neuron loss and near the toxic protein buildups characteristic of ALS.

"We saw that people with worse clinical ALS had more expression of complement genes, which are proteins that become activated as the body's first-line immune defense against a pathogen or damage to the body," Gate said.

Next steps for the research

Having identified a direct link between the immune system and ALS, Gate said the next step for his lab is to expand the research to include more patients and to more closely study the motor circuit, which is the neural command system that carries signals from the brain, through the spinal cord, to the muscles.

"Our next step is to map exactly how this immune reaction spreads throughout the entire motor circuit: from the brain, down through the spinal cord and out to the muscles," Gate said. "By profiling the motor circuit in depth, we'll get a much clearer picture of where and when inflammation drives faster progression, which should help us develop immune-targeted therapies that slow the disease and extend survival across ALS subtypes," Gate said.

The next step for Kiskinis' lab will be testing if there is a causal relationship between TDP-43 dysfunction and inflammation, which he suspects.

"We're trying to really define what is the mechanism that links TDP-43 dysfunction in nerve cells with inflammatory reactions," Kiskinis said.

Other Northwestern study authors include Ziyang Zhang, Lynn van Olst, Francesco Alessandrini, Matthew Wright, Alex Edwards, Jake Boles, Anait Nalbandian, Anne Forsyth, Nate Shepard, Thomas Watson, Evan Kaspi, Angeli Mittal, Joshua Kuruvilla, Natalie Piehl and Abhirami Ramakrishnan.

Funding for the study was provided by the National Institute on Neurological Disorders and Stroke and the National Institute on Aging, both of the National Institutes of Health (grants R01AG078713, R01NS104219, R01NS134166), the Les Turner ALS Foundation, the New York Stem Cell

Foundation, the Target ALS Foundation and the BrightFocus Foundation.

*Link will go live when the study publishes