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Pathogenesis of autoimmune neurodegeneration: What causes the immune system to destroy healthy neurons?

Final Report Summary - POAN (Pathogenesis of autoimmune neurodegeneration: What causes the immune system to destroy healthy neurons?)

The goal of the research has been to determine under which conditions an autoimmune attack on neurons can occur. There is a growing interest in neuroimmunology, and data suggests that disorders such as Parkinson's disease and schizophrenia have an autoimmune component. The ideal disease for studying this phenomenon is, however, the neurologic sleep disorder narcolepsy with cataplexy (NC), where the hypocretin (hcrt, a neuropeptide also known as orexin) producing neurons in hypothalamus are lost. Genetic and epidemiological evidence suggest that the specific hcrt cell loss is caused by an autoimmune attack, but the trigger of this is unknown.
A large part of the data that has led to the autoimmune hypothesis regards genetics and shows associations between different genetic variants in the immune system and a higher risk of narcolepsy. This project aimed to study the functional consequence of some of these variants. In particular we have studied how P2Y11 and DNMT1 might contribute to the pathological process. We study this using both cell culture, animal based research, and samples collected in the clinical setting from patients. This translational approach has already been a great advantage. Only by bridging the gap between experimental laboratory research and clinical research can we truly gain new knowledge about narcolepsy that has the potential of leading to new treatment.
P2Y11 is a G-protein coupled purinergic receptor and is activated by high concentrations of extracellular ATP. Since P2Y11 is not expressed in rodents, little is known about its specific functions. Our own data supports a role in immune regulation. We have shown that P2Y11 is involved in T-lymphocyte function, where it is upregulated upon stimulation and interacts with another ATP receptor - P2X7. While P2X7 induces cell death, P2Y11 protects against this. Direct effects of P2Y11 on hcrt cells or microglia are also possible, as virtually nothing is known about P2Y11 in the brain. So far we examined the distribution of P2Y11 in the brain, but unfortunately because of lack of specific antibodies, the question remains unanswered.
DNMT1 is a widely expressed DNA methyltransferase that maintains methylation patterns and mediates transcriptional repression. Based on the location of the narcolepsy-associated mutations it is likely that they affect DNA binding thus disturbing selective gene silencing. We have discovered that DNMT1 activity is important for regulating MHC class I expression in neuronal-like cell cultures.
The mechanisms studied here: T lymphocyte regulation, MHC expression in neurons, and neuronal cell death are relevant for a broad range of disorders where the immune system and/or neurons are involved. The results gained from this project will thus not only have great value for understanding and treatment of narcolepsy, but also for other autoimmune and neurodegenerative diseases.