The brain’s immune cells are supposed to be fighters. In Parkinson’s disease, they are: scan the brain tissue of a Parkinson’s patient and you will find microglia buzzing with inflammatory activity, mounting what looks, at least superficially, like a vigorous defence. So when Konstantin Khodosevich and his colleagues at the University of Copenhagen sat down to examine tissue from patients with multiple system atrophy (a neurodegenerative disease considerably more aggressive than Parkinson’s), they fully expected to find the same thing, only more so. They did not.
“We expected to see a very active immune system in the brain of patients with MSA, because the disease is so aggressive,” says Khodosevich, a professor at the Biotech Research and Innovation Centre. “But we found the opposite. It appears that the brain’s immune cells are dozy or exhausted, as if they have lost their ability to respond.”
The finding, published in Nature Communications, represents a striking reversal of what the field assumed about MSA. It’s one of those results that, once you see it, makes a kind of terrible sense, and raises an uncomfortable possibility about why the disease, for which there is still no treatment of any kind, progresses so much faster than its better-known cousin.
The Disease That Moves Faster Than Parkinson’s
Multiple system atrophy is rare, striking roughly one or two people in every hundred thousand, most of them in their mid-to-late fifties. It attacks the autonomic nervous system, disrupting balance, movement, blood pressure, and bladder control. The average time from diagnosis to death is somewhere between six and ten years, shorter than most comparable diseases. And yet, perhaps because it is rare, it has remained poorly understood. “MSA is a disease we know very little about,” says Susana Aznar, research leader at Bispebjerg and Frederiksberg Hospital and co-leader of the study.
Clinically, MSA can look a great deal like Parkinson’s at first. Both diseases involve the accumulation of a protein called alpha-synuclein in the brain. The difference is partly where: in Parkinson’s, this accumulation occurs mainly in neurons; in MSA, the protein collects in oligodendrocytes, the cells that wrap nerve fibres in myelin. Why that difference in location produces such dramatically different outcomes is something researchers are still working out.
What Khodosevich’s team wanted to understand was the cellular landscape underlying MSA’s ferocity. To do that, they turned to single-nucleus RNA sequencing, a technique that can map the activity of individual genes in individual cells, even in tissue taken from the deceased. “We take a very small piece of brain tissue the size of a fingernail and dissolve it into thousands of individual cell nuclei, which we analyze one by one,” says Rasmus Rydbirk, first author of the study, who is now a bioinformatician at the University of Southern Denmark. “It gives us a snapshot of what has happened in the brain at the end of the disease process.”
When the Cleaners Stop Cleaning
In total, the researchers analyzed more than 117,000 cells drawn from three groups: seven MSA patients, twelve Parkinson’s patients, and ten people without neurological disease. They focused on the striatum, a region of the brain involved in movement that is damaged in both conditions. What they found in the microglia (the brain’s resident immune cells, which ordinarily clear away cellular debris, misfolded proteins, and dying cells) was not inflammation. It was something closer to depletion.
Parkinson’s brains had microglia expressing markers associated with active, proinflammatory states. MSA brains had far fewer activated microglia, and the ones present showed gene expression patterns consistent with immune exhaustion or tolerance, a kind of immunological burnout seen in other contexts when immune cells are pushed too hard for too long. The MSA brains also showed more reactive astrocytes than the Parkinson’s tissue: another sign that the disease’s cellular environment is distinct, not simply more severe. When the team exposed lab-grown microglia to cerebrospinal fluid from MSA patients, the cells showed reduced phagocytic activity: they became sluggish at engulfing the debris they’re supposed to clear.
Aznar has a theory about how this might unfold over time. “We know from other studies that the immune system is very active at the beginning of the disease,” she says. “Therefore, we have a theory that the immune system may have been overactivated, causing the immune cells to become exhausted. And if the immune cells are not doing their job, the disease can develop more easily.” It is, in other words, possibly a story about an immune response that starts too hot and ends too cold, leaving the brain defenceless in between.
The study cannot establish cause and effect. The brain tissue was collected postmortem, offering a detailed picture of late-stage MSA but no window into how the situation developed. Sample sizes are also limited, largely because MSA is rare enough that donated brain tissue is genuinely hard to come by. The researchers are careful about this. What the data do offer is a high-resolution cellular map of how MSA differs from Parkinson’s in ways that go far beyond simple severity.
Looking for a Way In
For patients and their families, these distinctions carry real weight. Inge Vium, chair of the Danish association for Multiple System Atrofi, put it plainly: “It is devastating to be diagnosed with a fatal disease for which no treatments exist. That is why it is incredibly important that research into MSA is being carried out.” The association welcomes the new findings, she said, because understanding why the disease arises is a precondition for doing anything about it.
The microglial exhaustion hypothesis, if it holds up, opens at least one potential avenue. Immune cells that are depleted might, in principle, be reactivated, or at minimum protected, from reaching that state. “Our study shows that it is interesting to further investigate the role of microglia to see whether this could be a potential target for future medical treatment,” says Aznar. Whether that translates into anything clinically useful remains, for now, an open question. What the Copenhagen team has done is perhaps more modest but no less necessary: they’ve shown that the disease researchers thought they understood is, at the cellular level, doing something quite different from what they assumed. The quiet in the brain, it turns out, may be part of what’s killing it.
https://doi.org/10.1038/s41467-026-71525-6
Frequently Asked Questions
What is multiple system atrophy and how does it differ from Parkinson’s disease?
Multiple system atrophy is a rare, progressive neurological disease that attacks the autonomic nervous system and affects movement, balance, blood pressure, and bladder control. Like Parkinson’s, it involves the accumulation of the protein alpha-synuclein in the brain, but in MSA the protein builds up in oligodendrocytes (myelin-forming cells) rather than neurons. The disease tends to strike earlier and progress considerably faster than Parkinson’s, and there is currently no treatment or cure.
What did the researchers actually find in the brains of MSA patients?
Using single-nucleus RNA sequencing on postmortem brain tissue, the researchers found that the immune cells in MSA brains, known as microglia, appeared exhausted or inactive, in contrast to the activated, proinflammatory microglia seen in Parkinson’s brains. MSA brains also had more reactive astrocytes than Parkinson’s brains. When lab-grown microglia were exposed to cerebrospinal fluid from MSA patients, they showed a reduced ability to engulf cellular debris, suggesting the disease environment itself impairs immune function.
Why might the brain’s immune cells become exhausted in MSA?
The researchers’ working theory is that the immune system may be intensely active at the beginning of the disease, then become depleted by overactivity over time. This kind of immune exhaustion is seen in other biological contexts when immune cells are chronically overstimulated. If this is what happens in MSA, it could help explain why the disease progresses so rapidly: once the microglia stop clearing protein deposits and cellular debris, the damage may accelerate. The study cannot yet confirm this sequence, as the tissue samples were taken after death.
Could targeting microglia lead to a treatment for MSA?
It’s too early to say. The findings suggest microglia are worth investigating as a potential therapeutic target, since cells that have become exhausted might in principle be reactivated or shielded from reaching that state. However, the research is at an early stage, sample sizes are limited by the rarity of MSA, and the study cannot establish whether microglial dysfunction causes the disease’s severity or results from it. Further studies are needed before any clinical application could be considered.
How was the research conducted, and what are its limitations?
The team analysed postmortem striatal brain tissue from seven MSA patients, twelve Parkinson’s patients, and ten people without neurological disease, examining more than 117,000 individual cell nuclei using single-nucleus RNA sequencing. The main limitations are the relatively small sample sizes, inevitable given how rare MSA is, and the fact that postmortem tissue only captures a snapshot of the disease at its end stage rather than tracking how things evolved over time. The cause-and-effect relationship between microglial exhaustion and disease progression has not been established.
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