A groundbreaking study from the University of Bonn and the German Center for Neurodegenerative Diseases (DZNE) has revealed that inflammation in the brain may play a central role in the early progression of spastic paraplegia type 15 (SPG15), a rare hereditary neurodegenerative disorder. Conducted using a genetically modified mouse model and published in the Journal of Experimental Medicine, the research provides compelling evidence that immune system overactivation precedes neuronal degeneration—findings that may also shed light on the pathology of diseases like Alzheimer’s.
A New Focus on the Brain’s Immune Response
Spastic paraplegia type 15 is marked by the gradual deterioration of motor neurons, particularly in the central nervous system. Symptoms generally appear in late childhood or adolescence and begin with involuntary twitching and progressive paralysis of the legs. While the genetic mutation that causes SPG15—a defect in the SPG15 gene leading to an absence of a vital protein—is known, the precise cellular mechanisms that drive neuron loss have remained elusive.
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The new study, led by Professor Elvira Mass of the LIMES Institute at the University of Bonn, in collaboration with Dr. Marc Beyer from the DZNE and Professor Ralf Stumm from University Hospital Jena, explored whether the immune system could be a key player in the disease’s onset.
“There was existing evidence that inflammatory processes in the brain play a role in development of the disease,” said Dr. Beyer. “So we studied microglia, which are the immune cells of the brain, and also whether immune cells in bone marrow are additionally involved in the inflammatory response.”
Microscopic Insights Into Cellular Behavior
To trace immune activity, the researchers used genetically modified mice that carry the same SPG15 gene mutation as human patients. Their approach included labeling white blood cells derived from bone marrow with a fluorescent dye, allowing these to be distinguished from microglia under a microscope. This dual labeling enabled scientists to observe interactions between the two distinct immune cell populations in real time.
Microglia, the brain’s resident immune cells, undergo significant transformation very early in the disease process, even before any damage to neurons becomes detectable. These altered microglia, termed “disease-associated microglia,” begin to release signaling molecules that summon cytotoxic “killer” T cells from the bone marrow. Once activated, the T cells infiltrate the brain and participate in the destruction of other cells—effectively driving the inflammatory cascade that may ultimately damage neurons.
“This makes them distinguishable from microglia under a microscope,” explained Professor Mass. “This allowed us to study the interaction between these two cell populations at the individual cell level.”
A Shift in Understanding Disease Progression
The findings from this study challenge the conventional belief that neuronal damage is the first step in the development of SPG15. Instead, the evidence suggests that a misregulated immune response occurs at the very onset of the disease, long before neurons begin to die. This early inflammation could be the trigger that sets off the degenerative process, rather than merely a response to existing damage.
“Our data suggest that the early stages of the disease are driven not by the loss of motor neurons but rather by the severe, early immune response,” said Mass. “And that finding implies new therapeutic possibilities.”
Therapeutic Implications and Broader Impact
The implications of this discovery extend beyond SPG15. Neuroinflammation is also a key feature of other neurodegenerative diseases, including Alzheimer’s and Parkinson’s. While the underlying causes of these conditions may differ, the pattern of immune overactivation could represent a shared mechanism of damage.
“This type of immune dysregulation could be relevant in dementia as well, even though the genetic roots of the diseases are different,” noted Dr. Beyer.
Based on the new findings, the researchers suggest that early immune modulation could represent a potential therapeutic avenue. Drugs that suppress or regulate the immune system might be able to slow the progression of SPG15 if administered before extensive neuronal damage occurs.
An Interdisciplinary Approach and Cutting-Edge Technology
This complex study was made possible through a collaborative effort combining immunology, neurobiology, and advanced single-cell technologies. The project involved institutions from across Germany and Australia, including the University of Bonn, DZNE, University Hospital Jena, and the University of Melbourne.
“Only by combining the sciences of immunology and neurobiology with cutting-edge single-cell technology was it possible to shed light on this aspect of the development of spastic paraplegia type 15,” said Dr. Beyer.
The research was supported by funding from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), and the European Research Council (ERC). The study also benefitted from the support and infrastructure of the ImmunoSensation2 Cluster of Excellence at the University of Bonn, which emphasizes interdisciplinary cooperation in the study of immune-related diseases.
Looking Ahead: From Mouse Models to Human Trials
While the findings from the mouse model are promising, the researchers caution that further studies are needed to translate these insights into human treatments. Future work will likely focus on confirming whether the same inflammatory responses occur in human patients with SPG15 and whether immune-modulating therapies can meaningfully alter disease outcomes.
Still, the results mark a significant step forward in understanding not only this rare disease but also the broader connections between the immune system and neurodegeneration. By redefining what happens at the earliest stages of SPG15, the study opens the door to earlier diagnosis, more effective intervention, and perhaps one day, prevention of progression altogether.
As Professor Mass concluded, “Understanding that the immune system plays a leading role from the very beginning changes how we approach treatment. It’s no longer just about protecting neurons—it’s about preventing them from ever being attacked in the first place.”
