Same symptoms, different biology

Antwerp & Leuven, 14 Oct 20205 – A Belgian team has uncovered fundamental differences in the brain’s immune response between inherited and non-inherited forms of amyotrophic lateral sclerosis (ALS), despite looking almost identical in the clinic. The findings, published today in Nature Neuroscience, could reshape how patients are stratified for trials and how future therapies are targeted.

ALS is a deadly disease affecting approx. 1 in 400 adults. Patients are confronted with a gradually increasing loss of motor neurons, resulting in muscle weakness that rapidly spreads and worsens. Most patients die within a few years of first symptom onset. 

Two disease forms

As a neurologist at UZ Leuven, Prof. Philip Van Damme has seen hundreds of ALS patients and is all too familiar with the devastating toll it takes on patients and their loved ones. In his lab at KU Leuven, he studies the molecular and cellular underpinnings of the disease.

To better map the specific disease mechanisms in the context of the nervous system, he teamed up with Prof. Renzo Mancuso at the VIB-UAntwerp Center for Molecular Neurology. Mancuso has pioneered methods to study human-derived neurons and neuronal immune and support cells, called microglia and astrocytes respectively, to study how these different cells interact in the context of a healthy, or disease-affected, brain.

Together, Van Damme, Mancuso and their team members set out to map cell-by-cell changes in both the brain and the spinal cord of patients having a genetic mutation predisposing them to ALS, as well as patients with no known genetic link (so-called sporadic patients).

Two cellular stories

“We found that microglia, the brain’s immune cells, behave differently in sporadic ALS, versus a genetic form of ALS,” explains Van Damme. “While microglia clearly switch on into an active, ‘damage-responding’ state, in the case of sporadic ALS, the same microglia were less able to make this switch in the genetic cases under investigation.”

“Astrocytes were also affected,” adds Mancuso. Astrocytes from the inherited form of ALS displayed a dampened response compared to the sporadic ALS cases. “The evidence points towards impaired communication between microglia and astrocytes.”

Bottom line: although inherited ALS and sporadic ALS may look the same at the bedside, their cellular and molecular substrates differ, with direct implications for patient stratification and therapy selection.

A milestone for and thanks to patients

“This is the first integrated, side-by-side comparison of microglia and astrocyte states in genetic versus sporadic forms of ALS, and we confirm the key differences across human tissue, patient-derived cells, and in human cells transplanted into the context of a living (mouse) brain,” says Mancuso. “Our findings indicate that one-size-fits-all immunomodulatory approaches are unlikely to work in ALS.”

“This work would not be possible without the generosity of patients and families who donate brain and spinal cord tissue,” says Van Damme. “With today’s single-cell technologies, we can finally study ALS mechanisms in more detail in human tissue, and I’m convinced this will accelerate progress in the coming years.”

Publication

C9orf72 hexanucleotide repeat expansions impair microglial response in ALS. Masrori, Bijnens, Fumagalli et al. Nature Neuroscience 2025

The work was funded by the ALS Liga, ERC, FWO, KU Leuven (a.o. Opening the Future fund and ALS funds), BrightFocus Foundation, SAO, and VIB.