Narcolepsy is a life long disorder characterized by excessive daytime sleepiness, cataplexy and symptoms of abnormal Rapid Eye Movement (REM) sleep. It is a common disorder that affects 1 in 2,000 individuals in North America and Western Europe. Recent discoveries have provided firm evidence that narcolepsy/hypocretin deficiency is an autoimmune disorder affecting the brain, and more particularly hypocretin-expressing neurons, with resulting hypocretin loss causing sleep disturbances. In addition to the established role of HLA DQB1*0602, two additional immune-related susceptibility genes have now been identified: the T Cell Receptor Alpha locus, and an understudied purinergic receptor, P2RY11. Recent studies of patients close to disease onset have also demonstrated other autoimmune hallmarks: an increased presence of antistreptolysin-0 (ASO) antibody, implicating a role for streptococcal infections as a trigger for the autoimmune process, as well as the detection autoantibodies directed against the protein of TRIB2 in sera. In this project, we will examine how these molecular players are involved in the autoimmune pathogenesis of narcolepsy. T-cell receptor (TCR) loci are unique in that repertoire diversity is generated through somatic cell recombination of V, D, and J segments. The genetic association of the TCRA locus with narcolepsy strongly suggests the presence of one or more VJ recombinants that predispose to the disease. To study this possibility, we will first perform deep sequencing of the expressed TCR alpha/ beta chain repertoire to identify potential disease-associated TCR variants. Second, we will perform functional studies to determine how the newly identified purinergic receptor P2RY11, and narcolepsy-associated polymorphisms in the P2RY11 locus modulate immune function in controls and subjects with narcolepsy. We hypothesize that narcolepsy is the result of specific environmental exposures in genetically susceptible individuals and that specific bacterial infections could serve as a trigger for the disease. We will therefore characterize the autoantibody and post-infectious profile in narcolepsy sera close to disease onset. To do so, we will search for specific S. pyogenes DNA sequences, and perform bacterial 16S rRNA-based community-wide surveys in pharyngeal swab samples from narcolepsy (close to onset) versus controls. We will also screen sera of recent onset samples to search for autoantibodies directed against proteins likely to be enriched in hypocretin expressing neurons based on BAC-TRAP technology mRNA profiling results. As very few autoimmune disorders are known to directly target neurons, and immune-brain interactions are only starting to be studied, a better understanding of the pathophysiology of narcolepsy is likely to Illuminate the cause of other neuropsychiatric disorders with a neuroimmune component as well.

Public Health Relevance

Narcolepsy is a life long disorder characterized by excessive daytime sleepiness, cataplexy and symptoms of abnormal Rapid Eye Movement (REM) sleep. The cause of the disease is an autoimmune attack against the hypocretin producing cells in the brain. Our research is focused on understanding this process and preventing it from occurring. We also are seeking new treatment methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS023724-26
Application #
8517214
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
26
Fiscal Year
2013
Total Cost
$274,798
Indirect Cost
$87,416
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Plante, David T; Finn, Laurel A; Hagen, Erika W et al. (2016) Subjective and Objective Measures of Hypersomnolence Demonstrate Divergent Associations with Depression among Participants in the Wisconsin Sleep Cohort Study. J Clin Sleep Med 12:571-8
Kornum, Birgitte Rahbek; Pizza, Fabio; Knudsen, Stine et al. (2015) Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain Behav Immun 49:54-8
Kawai, Makoto; O'Hara, Ruth; Einen, Mali et al. (2015) Narcolepsy in African Americans. Sleep 38:1673-81
Wendt, Sabrina L; Welinder, Peter; Sorensen, Helge B D et al. (2015) Inter-expert and intra-expert reliability in sleep spindle scoring. Clin Neurophysiol 126:1548-56
Gottlieb, D J; Hek, K; Chen, T-H et al. (2015) Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. Mol Psychiatry 20:1232-9
Jacob, Louis; Leib, Ryan; Ollila, Hanna M et al. (2015) Comparison of Pandemrix and Arepanrix, two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development. Brain Behav Immun 47:44-57
Li, Jason; Moore 4th, Hyatt; Lin, Ling et al. (2015) Association of low ferritin with PLM in the Wisconsin Sleep Cohort. Sleep Med 16:1413-8
Ollila, Hanna M; Ravel, Jean-Marie; Han, Fang et al. (2015) HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet 96:136-46
de Lecea, Luis (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367-78
Holm, Anja; Lin, Ling; Faraco, Juliette et al. (2015) EIF3G is associated with narcolepsy across ethnicities. Eur J Hum Genet 23:1573-80

Showing the most recent 10 out of 52 publications