When the Immune System Goes Quiet: What C9orf72 ALS Is Teaching Us
January 8, 2026
For years, inflammation has been one of the central villains in the ALS story.
Overactive immune cells. Runaway neuroinflammation. Damage amplified by a system stuck in overdrive.
But what if, in some forms of ALS, the problem isn’t that the immune system is too loud, but that it’s barely speaking at all?
That’s the question at the heart of new work led by Dr. Pegah Masrori, a Target ALS–funded investigator whose research is reshaping how we understand immune dysfunction in ALS, particularly in patients with C9orf72-linked disease, the most common genetic cause of ALS.
Her team’s recent paper, C9orf72 hexanucleotide repeat expansions impair microglial response in ALS, published in Nature Neuroscience, offers a striking conclusion: C9-linked ALS follows a fundamentally different immune trajectory than sporadic ALS.
Microglia, Reconsidered
Microglia are the brain’s resident immune cells. They patrol, clean up debris, respond to injury, and support neurons under stress. In many ALS models, microglia shift into activated or inflammatory states as disease progresses.
But when Masrori and colleagues analyzed single-nucleus transcriptomes from the spinal cord and motor cortex of ALS patients, they saw something unexpected.
“What was most striking was that C9orf72-linked ALS did not map onto any of the classical inflammatory microglial states described in ALS models to date,” Masrori explained. “Rather than excessive immune activation, we observed a failure to fully engage protective microglial programs.”
In other words, C9 microglia weren’t hyperactive. They were transcriptionally blunted, metabolically constrained, and functionally incomplete.
This wasn’t just a subtle shift. Compared to sporadic ALS, where immune pathways ramp up aggressively, C9 microglia appeared stuck, unable to transition into states needed to respond to damage.
The Cost of a Muted Response
At the center of this dysfunction is C9orf72 haploinsufficiency. While the gene is widely known for its toxic repeat expansions in neurons, Masrori’s work reinforces something equally critical: C9orf72 is highly expressed in microglia, where it plays a foundational role in endolysosomal trafficking, autophagy, and immune receptor signaling.
At the center of this dysfunction is C9orf72 haploinsufficiency, but not where the field first expected it to matter most. While C9orf72 is widely associated with toxic repeat expansions in neurons, researchers have long known that the gene is actually most highly expressed in microglia, even more so than in neurons, astrocytes, or other brain cell types.
What Masrori’s study made clear is why that matters. Using single-nucleus RNA sequencing on postmortem C9-ALS brain tissue, her team was among the first to directly examine what happens inside human microglia compared with other cell types. They found that microglia show a reduction in overall C9orf72 RNA, leading to haploinsufficiency and a marked impairment of core microglial functions. These included disrupted lysosomal activity, the cellular system responsible for clearing debris and aggregated proteins, as well as broader deficits in immune receptor signaling.
To push these findings further, the team used an elegant in vivo approach: transplanting human C9 knockout or repeat-expansion–expressing microglial precursor cells into mice, then later isolating the mature microglia. Even in this controlled setting, C9orf72 levels remained low, alongside reduced expression of immune-related genes. Together, these state-of-the-art human and transplant models confirmed that C9orf72 haploinsufficiency fundamentally compromises microglial competence, leaving the brain’s primary immune cells underpowered when they are needed most.
“Haploinsufficiency does not merely attenuate one pathway,” Masori said, “It destabilizes the core infrastructure that enables microglia to transition between functional states.”
Without those transitions, microglia fail to adopt damage-responsive or phagocytic identities, Masrori said. The result isn’t immune toxicity; it’s immune absence at critical moments of neuronal vulnerability.
Why Endolysosomal Pathways Matter
One of the most consistent signals across Masrori’s datasets was disruption of endolysosomal and phagocytic pathways. These are not niche cellular functions. They are central to what makes microglia microglia.
These pathways allow immune cells to:
- Clear protein aggregates and dying cells
- Remodel synapses across the lifespan
- Coordinate with astrocytes to maintain neural health
“In C9-linked ALS, disruption of these pathways locks microglia into a dysfunctional intermediate state, neither inflammatory nor reparative,” Masrori said. “Neurons, which rely on continuous extrinsic quality control, are left exposed to cumulative stress.”
Over time, that exposure may be just as damaging as runaway inflammation.
Rethinking Inflammation as a Target
This work has direct implications for therapy.
The ALS field has largely treated inflammation as something to suppress. That approach makes sense in some contexts. But Masrori’s findings argue strongly against a one-size-fits-all strategy.
“In C9-linked ALS, the goal may be to restore microglial competence rather than dampening immune activity,” she explained.
That means therapies designed to correct cellular state, improve lysosomal function, and restore immune sensing, rather than blunt the immune system wholesale. It also reinforces the need for patient stratification, where treatments are matched to the underlying biology, not just the diagnosis.
From Single Cells to Systems
The study also mapped disrupted ligand–receptor signaling between microglia and astrocytes, revealing how immune dysfunction in one cell type can ripple across the entire glial ecosystem.
Astrocytes are not passive bystanders in the brain. Under healthy conditions, they support neurons by regulating neurotransmitters, maintaining metabolic balance, and helping preserve the blood–brain barrier. In ALS, however, astrocytes can become reactive, shifting into a state where they release inflammatory signals and toxic factors that place additional stress on already vulnerable neurons.
Crucially, astrocytes do not operate in isolation. Their behavior is shaped by ongoing cues from microglia. When microglial signaling is muted or distorted, as occurs with C9orf72 haploinsufficiency, astrocytes may fail to receive the signals that normally restrain excessive inflammation. The result is a maladaptive feedback loop: underperforming microglia and overactive astrocytes amplifying neuronal damage.
“By restoring microglial function upstream, we may be able to normalize astrocyte behavior downstream,” Masrori said. “This shifts therapeutic thinking toward reconstructing glial ecosystems.”
This systems-level perspective is exactly what the Target ALS ecosystem was built to support: integrating genetics, single-cell biology, model systems, and patient-derived data to reveal multi-cellular mechanisms that would remain invisible when studied in isolation.
The Bigger Picture
Masrori’s work delivers a clear message: ALS is not a single disease with a single immune profile.
In some patients, inflammation may be excessive. In others, it may be insufficient. And in C9-linked ALS, immune hypofunction may be a primary driver of disease progression, explained Masori.
Key insight: ALS is not just a neuronal disease. It is an immune and cellular ecosystem disorder. Understanding how specific genes like C9orf72 reshape that ecosystem is essential to designing targeted, effective treatments. With continued support from Target ALS, this kind of precision biology brings us closer to therapies that meet patients where their disease truly begins, not where we once assumed it lived.
