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RESEARCH
Narcolepsy and the loss of hypocretin neurons
Narcolepsy affects 1 out of 2000 individuals and is characterized by severe, irresistible daytime sleepiness, cataplexy, and abnormal sleep patterns. The disease has severe consequences for the patient, is chronic, and can only be symptomatically treated.
AUTOIMMUNE HYPOTHESIS OF NARCOLEPSY TYPE 1.
The most important elements in the current hypothesis of narcolepsy type 1 (NT1) pathogenesis include T cells, microglia and antibodies. If autoreactive T cells and antibodies enter the brain, an immune reaction that leads to the destruction of hypocretin neurons in the lateral hypothalamus could be started. The most likely mediators of the loss of hypocretin neurons are cytotoxic CD8+ T cells, which could provide pro-apoptotic signals to the hypocretin neurons, leading to neuronal loss. Although CD4+ T cells can enter the healthy brain, antibodies do not cross the blood–brain barrier under normal circumstances and only cross if the blood–brain barrier is compromised (dashed arrow) by a pathological event. In pathological conditions, autoantibodies can enter the brain, and, by binding to hypocretin neurons or their downstream targets, they could potentially have a role by activating the local microglia.
Narcolepsy. Kornum et al. Nature Reviews Disease Primers 2017
Defects in the P2Y11 receptor can lead to narcolepsy. In red are shown the amino acids in the P2Y11 protein that we have discovered are mutated in some narcolepsy patients.
Kornum et al. Nature Genetics 2011, Degn et al. Brain 2017.
P2Y11
In our quest to understand what causes narcolepsy, we study the immune system of patients. We hypothesise that some of the proteins genetically associated with narcolepsy plays a central role in the disease process, and this is what we study. Importantly our work has shown that defects in the purinergic receptor P2Y11 predisposes to narcolepsy. P2Y11 is a dual Gs-Gq-protein coupled purinergic receptor that is activated by high concentrations of extracellular ATP. The receptor is highly important for the normal function of immune cells, and we are now studying how the narcolepsy associated mutations affects the immune system.AUTOIMMUNITY
We have tested whether hypocretin itself might be the target in the autoimmune destruction of the hypocretin producing neurons. This is not the case.
Kornum et al. J Neuroimmunology 2017
MHC class I subtypes are differentially regulated in neurons.We here show neurons in culture (pink), with MHC class I expression (green). Blue is DAPI staining of the nuclei.
MHC Class I in Neurons
In order for cytotoxic CD8+ T cells to damage a cell, they must recognize an antigen presented by MHC-I. MHC-I expression is absent or weak in neurons of the healthy mature brain, but neurons may upregulate and express MHC-I in response to immune stimuli. Data from our lab and from several previous studies have found that pro-inflammatory cytokines induce MHC-I expression in vitro in neurons, in vivo in response to systemic infection, and in diseases such as multiple sclerosis (MS). Non-immune stimuli, such as electrical silencing or stimulation, can also induce MHC-I in vitro under certain conditions. However, we know little about regulation of MHC-I expression in hcrt neurons.We hypothesise that not only immune stimuli but also neuronal activation will upregulate MHC-I expression in hypocretin neurons.Narcolepsy in our research
Narcolepsy is caused by the patients losing their hypocretin producing neurons in hypothalamus. This loss leads to a lack of the neuropeptide hypocretin and subsequently disturbed sleep regulation. This is likely due to an autoimmune destruction of the neurons. Both genetic and environmental predisposing factors point in this direction. We aim to discover what causes narcolepsy.
An introduction to our research. Video of the Lundbeck Foundation