Concomitant loss of dynorphin, NARP, and orexin in narcolepsy - PubMed (original) (raw)
Concomitant loss of dynorphin, NARP, and orexin in narcolepsy
A Crocker et al. Neurology. 2005.
Abstract
Background: Narcolepsy with cataplexy is associated with a loss of orexin/hypocretin. It is speculated that an autoimmune process kills the orexin-producing neurons, but these cells may survive yet fail to produce orexin.
Objective: To examine whether other markers of the orexin neurons are lost in narcolepsy with cataplexy.
Methods: We used immunohistochemistry and in situ hybridization to examine the expression of orexin, neuronal activity-regulated pentraxin (NARP), and prodynorphin in hypothalami from five control and two narcoleptic individuals.
Results: In the control hypothalami, at least 80% of the orexin-producing neurons also contained prodynorphin mRNA and NARP. In the patients with narcolepsy, the number of cells producing these markers was reduced to about 5 to 10% of normal.
Conclusions: Narcolepsy with cataplexy is likely caused by a loss of the orexin-producing neurons. In addition, loss of dynorphin and neuronal activity-regulated pentraxin may contribute to the symptoms of narcolepsy.
Figures
Figure 1
Prodynorphin and NARP co-localize with orexin. A) In coronal hypothalamic sections from a control subject, most neurons containing orexin-IR also produce prodynorphin mRNA (black circles) and are mainly located in the lateral and posterior hypothalamic areas (LHA and PHA) above and around the fornix (fx). A few neurons apparently containing only orexin (white circles) or prodynorphin (grey circles) are scattered within this region, and a separate group of neurons producing only prodynorphin mRNA lie in the paraventricular nucleus of the hypothalamus (PVH). B) Neurons double-labeled for orexin-B and NARP (black circles) have a similar distribution. This region also contains a few neurons apparently containing only orexin-B (white circles) or only NARP (grey circles). The PVH contains many cells producing only NARP. Other abbreviations: 3V, third ventricle; opt, optic tract; LT, lateral tuberal nucleus; VMH, ventromedial hypothalamic nucleus; DMH, dorsomedial hypothalamic nucleus; TM, tuberomammillary nucleus; SO, supraoptic nucleus; st, stria terminalis; IGP, internal globus pallidus; MMC, mammillary nucleus, magnocellular part; SUM, supramammillary nucleus; cp, cerebral peduncle.
Figure 2
Loss of prodynorphin and NARP in narcolepsy. A) Sections from a subject with narcolepsy show a marked reduction in the number of neurons labeled for orexin (white circles). Within the orexin field, the number of neurons expressing prodynorphin mRNA (grey circles) is also reduced, but the paraventricular nucleus still contains a moderate number of prodynorphin-labeled cells. B) This individual also has a substantial loss of neurons double-labeled for orexin-B and NARP (black circles) within the orexin neuron field. This region also contains a few cells apparently containing only orexin-B (white circles) or only NARP (grey circles), but the PVH still contains a large number of neurons producing NARP alone.
Comment in
- Narcolepsy: selective hypocretin (orexin) neuronal loss and multiple signaling deficiencies.
Bassetti CL. Bassetti CL. Neurology. 2005 Oct 25;65(8):1152-3. doi: 10.1212/01.wnl.0000186118.96509.94. Neurology. 2005. PMID: 16247037 No abstract available.
Similar articles
- Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy.
Blouin AM, Thannickal TC, Worley PF, Baraban JM, Reti IM, Siegel JM. Blouin AM, et al. Neurology. 2005 Oct 25;65(8):1189-92. doi: 10.1212/01.wnl.0000175219.01544.c8. Epub 2005 Aug 31. Neurology. 2005. PMID: 16135770 Free PMC article. - Narcolepsy: selective hypocretin (orexin) neuronal loss and multiple signaling deficiencies.
Bassetti CL. Bassetti CL. Neurology. 2005 Oct 25;65(8):1152-3. doi: 10.1212/01.wnl.0000186118.96509.94. Neurology. 2005. PMID: 16247037 No abstract available. - Orexin (hypocretin) neurons contain dynorphin.
Chou TC, Lee CE, Lu J, Elmquist JK, Hara J, Willie JT, Beuckmann CT, Chemelli RM, Sakurai T, Yanagisawa M, Saper CB, Scammell TE. Chou TC, et al. J Neurosci. 2001 Oct 1;21(19):RC168. doi: 10.1523/JNEUROSCI.21-19-j0003.2001. J Neurosci. 2001. PMID: 11567079 Free PMC article. - Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system.
Nishino S, Kanbayashi T. Nishino S, et al. Sleep Med Rev. 2005 Aug;9(4):269-310. doi: 10.1016/j.smrv.2005.03.004. Sleep Med Rev. 2005. PMID: 16006155 Review. - Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy.
Liblau RS, Vassalli A, Seifinejad A, Tafti M. Liblau RS, et al. Lancet Neurol. 2015 Mar;14(3):318-28. doi: 10.1016/S1474-4422(14)70218-2. Epub 2015 Feb 16. Lancet Neurol. 2015. PMID: 25728441 Review.
Cited by
- Development of Novel 11C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.
Rong J, Yamasaki T, Li Y, Kumata K, Zhao C, Haider A, Chen J, Xiao Z, Fujinaga M, Hu K, Mori W, Zhang Y, Xie L, Zhou X, Collier TL, Zhang MR, Liang S. Rong J, et al. ACS Med Chem Lett. 2023 Sep 26;14(10):1419-1426. doi: 10.1021/acsmedchemlett.3c00320. eCollection 2023 Oct 12. ACS Med Chem Lett. 2023. PMID: 37849554 Free PMC article. - Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy.
Seifinejad A, Ramosaj M, Shan L, Li S, Possovre ML, Pfister C, Fronczek R, Garrett-Sinha LA, Frieser D, Honda M, Arribat Y, Grepper D, Amati F, Picot M, Agnoletto A, Iseli C, Chartrel N, Liblau R, Lammers GJ, Vassalli A, Tafti M. Seifinejad A, et al. Proc Natl Acad Sci U S A. 2023 May 9;120(19):e2220911120. doi: 10.1073/pnas.2220911120. Epub 2023 May 1. Proc Natl Acad Sci U S A. 2023. PMID: 37126681 Free PMC article. - Lateral Hypothalamus Corticotropin-releasing Hormone Receptor-1 Inhibition and Modulating Stress-induced Anxiety Behavior.
Eghtesad M, Elahdadi Salmani M, Lashkarbolouki T, Goudarzi I. Eghtesad M, et al. Basic Clin Neurosci. 2022 May-Jun;13(3):373-384. doi: 10.32598/bcn.2021.445.3. Epub 2022 May 1. Basic Clin Neurosci. 2022. PMID: 36457881 Free PMC article. - OX2R-selective orexin agonism is sufficient to ameliorate cataplexy and sleep/wake fragmentation without inducing drug-seeking behavior in mouse model of narcolepsy.
Yamamoto H, Nagumo Y, Ishikawa Y, Irukayama-Tomobe Y, Namekawa Y, Nemoto T, Tanaka H, Takahashi G, Tokuda A, Saitoh T, Nagase H, Funato H, Yanagisawa M. Yamamoto H, et al. PLoS One. 2022 Jul 22;17(7):e0271901. doi: 10.1371/journal.pone.0271901. eCollection 2022. PLoS One. 2022. PMID: 35867683 Free PMC article. - Fluid markers of synapse degeneration in synucleinopathies.
Cervantes González A, Belbin O. Cervantes González A, et al. J Neural Transm (Vienna). 2022 Feb;129(2):187-206. doi: 10.1007/s00702-022-02467-8. Epub 2022 Feb 11. J Neural Transm (Vienna). 2022. PMID: 35147800 Review.
References
- Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Medicine. 2000;6(9):991–997. - PubMed
- Mignot E, Lammers G, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59(10):1553–1562. - PubMed
- Chabas D, Taheri S, Renier C, Mignot E. The genetics of narcolepsy. Annu Rev Genomics Hum Genet. 2003;4:459–483. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- R01 MH062589-04/MH/NIMH NIH HHS/United States
- NS23724/NS/NINDS NIH HHS/United States
- R01 MH062589/MH/NIMH NIH HHS/United States
- P50 NS023724/NS/NINDS NIH HHS/United States
- MH62589/MH/NIMH NIH HHS/United States
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases