Narcolepsy affects 1 out of 2000 individuals and is characterized by severe, irresistible daytime sleepiness, cataplexy, and abnormal sleep patterns. The disease causes significant distress and can only be symptomatically treated. Some narcolepsy symptoms are seen in patients with intact hypocretin cells, but cataplexy is specific to narcolepsy with hypocretin deficiency.
Genetic associations in narcolepsy
Another approach for discovering novel disease pathways is to search for informative genetic associations.
Using state of the art methods, Birgitte R. Kornum discovered (during her post doc at Dr. Emmanuel Mignot’s laboratory) a new genetic association in narcolepsy with a common variant located in the P2RY11 gene.
Complementing this finding we recently found that missense mutations in DNMT1 cause a very rare inheritable form of narcolepsy - Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy (ADCA-DN). ADCA-DN is characterized by late onset cerebellar ataxia, sensory neuronal deafness, narcolepsy, and other symptoms. Cerebrospinal fluid hypocretin is low suggesting that loss of hcrt cells causes the narcolepsy phenotype.
One of the most exciting aspects of this finding is that since DNMT1 regulates both neurodegeneration and autoimmunity, understanding the mechanisms behind ADCA-DN could be essential for understanding neuronal autoimmunity in narcolepsy and in general.
P2RY11 and DNMT1
P2Y11 is a dual Gs-Gq-protein coupled purinergic receptor that is activated by high concentrations of extracellular ATP. DNMT1 is a widely expressed DNA methyltransferase that maintains methylation patterns and mediates transcriptional repression.
Because both ATP signaling and DNA methylation regulates several cell functions, it is difficult to pinpoint which function of P2Y11 and DNMT1 might be relevant for type 1 narcolepsy.
When combining the current knowledge about these two proteins with knowledge about autoimmunity and neurodegeneration three candidate functions emerge: Regulation of T cells, MHC class I expression in neurons, and neuronal apoptosis.
These are the focus points of our projects.