title: Nitric oxide mediates selective degeneration of hypothalamic orexin neurons through dysfunction of protein disulfide isomerase.
abstract: We addressed the role of nitric oxide (NO) in orexin neuron degeneration that has been observed under various pathological conditions. Administration of an NO donor NOC18 (50 nmol) into the third ventricle of mice resulted in a significant decrease of orexin-immunoreactive (-IR) neurons, in contrast to a modest change in melanin-concentrating hormone-IR neurons. In addition, NOC18 promoted formation of orexin-A-IR aggregates within orexin neurons. An endoplasmic reticulum stress inducer tunicamycin replicated the effect of NOC18 with regard to decrease of orexin-IR neurons and formation of aggregates. We also found that NOC18 caused an increase in S-nitrosation of protein disulfide isomerase (PDI) and a decrease in PDI activity in hypothalamic tissues. Moreover, PDI inhibitors, such as cystamine and securinine, caused a selective decrease of orexin neurons and promoted formation of orexin-A-IR aggregates. Aggregate formation in orexin-IR neurons was also induced by local injection of small interfering RNA targeting PDI. Interestingly, sleep deprivation for 7 consecutive days induced a selective decrease of orexin-IR neurons, which was preceded by aggregate formation in orexin-IR neurons and an increase in S-nitrosated PDI in the hypothalamus. Activity of neuronal NO synthase (nNOS)-positive neurons in the lateral hypothalamus as assessed by c-Fos expression was elevated in response to sleep deprivation. Finally, sleep deprivation-induced decrease of orexin-IR neurons, formation of aggregates, and S-nitrosation of PDI were not observed in nNOS knock-out mice. These results indicate that nNOS-derived NO may mediate specific pathological events in orexin neurons, including neuropeptide misfolding via S-nitrosation and inactivation of PDI.
authors.affiliation: Department of Chemico-Pharmacological Sciences and Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Obukuro
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nobunaga
authors.forename: Moeko
authors.initials: M
authors.lastname: Takigawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morioka
authors.forename: Akinori
authors.initials: A
authors.lastname: Hisatsune
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Isohama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
mesh_terms: D000818:Animals; D002452:Cell Count; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007031:Hypothalamus / Q000166:cytology* / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000209:etiology; D009479:Neuropeptides / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000633:toxicity; D015538:Nitrosation / Q000187:drug effects / Q000235:genetics; D009603:Nitroso Compounds / Q000633:toxicity; D000068797:Orexins; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C093285:NOC 18; D009479:Neuropeptides; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D000068797:Orexins; D009569:Nitric Oxide; D009252:NADPH Dehydrogenase; D019704:Protein Disulfide-Isomerases
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