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Spastic paraplegia type 15 leads to movement challenges starting in adolescence, potentially resulting in the necessity for a wheelchair. Research published in the Journal of Experimental Medicine reveals that the brain significantly influences this rare hereditary condition by excessively activating the immune system. This study was conducted by researchers at the University of Bonn and the German Center for Neurodegenerative Diseases (DZNE). The implications of these findings could extend to understanding Alzheimer’s disease and other neurodegenerative disorders.
Characterized by the gradual degeneration of neurons in the central nervous system that control movement, spastic paraplegia type 15 typically presents initial symptoms in late childhood. These symptoms initially affect the legs, leading to uncontrollable twitching and paralysis. “The precise mechanisms behind the neuronal degeneration remain unclear,” notes Professor Elvira Mass from the LIMES Institute at the University of Bonn. “Our study focused on examining the immune system’s potential involvement in this degeneration.”
Professor Mass, along with Dr. Marc Beyer from DZNE and Professor Ralf Stumm from University Hospital Jena, led this comprehensive investigation. The condition arises from a defect in the SPG15 gene, which is responsible for producing a critical protein. Due to this genetic defect, the protein is not synthesized effectively.
Severe inflammation preceding the onset of cell damage
The research team utilized mice with the same genetic mutation to explore the disease’s inflammatory processes. “Prior evidence suggested that inflammation in the brain contributes to the disease’s progression,” Dr. Beyer explains. They focused on studying microglia, the brain’s immune cells, and the role of bone marrow-derived immune cells in this inflammatory response.
White blood cells, crucial in combating disease, originate in the bone marrow and can migrate to the brain through the bloodstream. Conversely, microglia are pre-established in the brain during embryonic development. The researchers achieved a significant milestone by distinguishing bone marrow-derived cells using a fluorescent dye. “This differentiation allowed us to observe the interactions between these two cell populations at a cellular level,” Mass explains.
Analysis revealed that microglia undergo significant alterations in the early phases of the disease, occurring well before any neuronal damage occurs. They transform into what are termed “disease-associated microglia,” which release signaling substances that attract cytotoxic “killer” T cells from the bone marrow, leading to further cell destruction. The interaction between these cell types and their signaling pathways accelerates the inflammatory response.
Findings open up new therapeutic possibilities
“Our findings indicate that the early stages of the disease are primarily driven by an intense immune response rather than the loss of motor neurons,” Mass notes, suggesting that this insight may pave the way for new therapeutic approaches. Immune-modulating drugs could potentially slow the disease’s progression.
While spastic paraplegia is caused by different factors than dementia, both conditions appear to involve similar immune system disruptions, making this research particularly relevant. The findings stem from collaborative efforts within the ImmunoSensation2 Cluster of Excellence, where interdisciplinary work in immunology and neurobiology, combined with advanced single-cell technologies, has been crucial in elucidating aspects of spastic paraplegia type 15’s progression.
The study involved collaboration among the German Center for Neurodegenerative Diseases and the universities of Bonn, Jena, and Melbourne, with financial support from grants provided by the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), and the European Research Council (ERC).
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