2006 Fiscal Year Final Research Report Summary
Study of the autoimmune mechanism in narcolepsy using gene expressional profiling
| Project/Area Number |
17390324
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Psychiatric science
|
|---|
| Research Institution | Tokyo Metropolitan Organization for Medical Research |
|---|
Principal Investigator |
HONDA Makoto Tokyo Metropolitan Organization for Medical Research, Tokyo Institute of Psychiatry, Research Director, 東京都精神医学総合研究所, 副参事研究員 (50370979)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TANAKA Susumu Tokyo Metropolitan Organization for Medical Research, Tokyo Institute of Psychiatry, Post-Doctoral fellow, 東京都精神医学総合研究所, 研究員 (30399472)
KAWASHIMA Minae The University of Tokyo, Graduate School of Medicine, Department of Sleep Analysis, Staff, 大学院医学系研究科・寄附講座, 教員 (00396706)
HONDA Yutaka Neuropsychiatric Research Institute, President, 理事長 (90010305)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Keywords | gene expressional profiling / narcolepsy / autoantibody |
|---|
| Research Abstract |
Narcolepsy is a common sleep disorder characterized by excessive daytime sleepiness, cataplexy (sudden loss of muscle tone triggered by emotion) and other manifestations of abnormal REM sleep. The pathophysiology of narcolepsy involves the HLA and hypocretin neurotransmission. Almost all cases with narcolepsy share a common HLA allele, DQB1^*0602 suggesting an autoimmune basis for the disorder. Over 90% of narcolepsy cases are associated with a dramatic decrease in hypocretin-1 (HCRT1) in the cerebrospinal fluid. Immunohistochemical studies also revealed a more than 90% decrease in HCRT cell count in the hypothalamus of narcoleptic subjects. In this study, we have used postmortem human brain samples to compare the transcriptome of narcoleptic versus control subjects. Our primary goal was to identify other genes that may be dysregulated in the posterior hypothalamus of narcoleptic patients. We have also developed a novel radioligand binding assay system to address the question whether a
… More
utoantibodies against hypocretin and hypocretin receptors and other identified narcolepsy-related genes were involved in narcolepsy pathophysiology or not.
Out of 11 upregulated and 35 downregulated genes in narcolepsy, 9 downregulated genes were verified with quantitative RT-PCR. Hypocretin was the most downregulated gene. One of these 9 genes, insulin-like growth factor binding protein(IGFBP), was confirmed to be highly expressed in hypocretin neurons. Sera from narcolepsy and control subjects were compared for the presence of autoantibodies against hypocretin, its receptors, and IGFBP. We detected autoantibodies against hypocretin in 3 patients, hcrtr1 in 1 patient, and hcrtr2 in 5 patients, but the finding was not disease specific. We were unable to find autoantibodies against IGFBP. Our results do not support the hypothesis that autoantibody-mediated dysfunction in the hypocretin system underlies the pathophysiology of narcolepsy. However IGFBP is known to have proapoptotic properties and may be involved in the pathogenesis of narcolepsy. Less
|
