RT Journal Article
SR Electronic
T1 Nitric Oxide Mediates Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide Isomerase
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12557
OP 12568
DO 10.1523/JNEUROSCI.0595-13.2013
VO 33
IS 31
A1 Kanae Obukuro
A1 Mizuki Nobunaga
A1 Moeko Takigawa
A1 Hiroshi Morioka
A1 Akinori Hisatsune
A1 Yoichiro Isohama
A1 Hiroaki Shimokawa
A1 Masato Tsutsui
A1 Hiroshi Katsuki
YR 2013
UL http://www.jneurosci.org/content/33/31/12557.abstract
AB 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.