Impaired chemosensitivity and perception of dyspnoea in Parkinson's disease

Oda, Hiroshi; Okabe, Shinichi; Kikuchi, Yoshihiro; Tsuda, Takuya; Itoyama, Yasuto

doi:10.1016/s0140-6736(00)02638-6

Cited by 79 publications

(73 citation statements)

References 5 publications

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“…but normal ventilatory responses to hypercapnia (Onodera et al 2000), which is similar to the altered ventilatory responses seen in heme oxygenase-2-deficient mice (Adachi et al 2004). It is therefore conceivable that heme oxygenase-2, an essential enzyme in heme catabolism, may be involved in the survival of the dopaminergic neurons in the substantia nigra.…”

Section: Altered Ventilatory Responses In Bw Mice Lacking Melanocytesmentioning

confidence: 63%

“…Altered functions of the central chemosensors may be involved in the pathophysiology of various diseases, including bronchial asthma Yamauchi 2006), chronic obstructive pulmonary disease (Takemura et al 2005), Parkinson's disease (Onodera et al 2000), and protozoan infection, such as sleeping sickness (African trypanosomiasis) caused by Trypanosoma brucei (Pentreath et al 1990;Kubata et al 2000) and cerebral malaria caused by Plasmodium falciparum (Turner 1997;Takeda et al 2005). For example, patients with Parkinson's disease showed blunted ventilatory responses to hypoxia Central O 2 sensor is also shown (a small red oval).…”

Section: Altered Ventilatory Responses In Bw Mice Lacking Melanocytesmentioning

confidence: 99%

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Neuroendocrine Functions of Melanocytes: Beyond the Skin-Deep Melanin Maker

Takeda

Takahashi

Shibahara

2007

Tohoku J. Exp. Med.

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The skin is armored with "dead cells", the stratum corneum, and is continuously exposed to external stressful environments, such as atmospheric oxygen, solar radiations, and thermal and chemical insults. Melanocytes of neural crest origin are located in the skin, eye, inner ear, and leptomeninges. Melanin pigment in the skin is produced by melanocytes under the influence of various endogenous factors, derived from neighboring keratinocytes and underlying fibroblasts. The differentiation and functions of melanocytes are regulated at multiple processes, including transcription, RNA editing, melanin synthesis, and the transport of melanosomes to keratinocytes. Impairment at each step causes the pigmentary disorders in humans, with the historical example of oculocutaneous albinism. Moreover, heterozygous mutations in the gene coding for microphthalmia-associated transcription factor, a key regulator for melanocyte development, are associated with Waardenburg syndrome type 2, an auditory-pigmentary disorder. Sun tanning, melasma, aging spots (lentigo senilis), hair graying, and melanoma are well-known melanocyte-related pathologies. Melanocytes therefore have attracted much attention of many ladies, makeup artists and molecular biologists. More recently, we have shown that lipocalin-type prostaglandin D synthase (L-PGDS) is expressed in melanocytes but not in other skin cell types. L-PGDS generates prostaglandin D 2 and also functions as an inter-cellular carrier protein for lipophilic ligands, such as bilirubin and thyroid hormones. Thus, melanocytes may exert hitherto unknown functions through L-PGDS and prostaglandin D 2 . Here we update the neuroendocrine functions of melanocytes and discuss the possible involvement of melanocytes in the control of the central chemosensor that generates respiratory rhythm.heme; hypoxia; lipocalin-type prostaglandin D synthase; melanocyte; microphthalmia-associated transcription factor

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Section: Altered Ventilatory Responses In Bw Mice Lacking Melanocytesmentioning

confidence: 63%

Section: Altered Ventilatory Responses In Bw Mice Lacking Melanocytesmentioning

confidence: 99%

Neuroendocrine Functions of Melanocytes: Beyond the Skin-Deep Melanin Maker

Takeda

Takahashi

Shibahara

2007

Tohoku J. Exp. Med.

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“…5). Altered ventilatory responses to hypoxia may play a critical role in asthma, diabetes, Parkinson's disease, sleep-related breathing disorders, and sudden infant death syndrome (6)(7)(8). We hypothesized that HIF-1␣ is required for carotid body function and ventilatory adaptation to chronic hypoxia.…”

mentioning

confidence: 99%

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Kline

Peng

Manalo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

237

216

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To investigate whether the transcriptional activator hypoxiainducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O 2-regulated HIF-1␣ subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a ϩ/Ϫ mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wild-type mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded, whereas carotid bodies from Hif1a ϩ/Ϫ mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a ϩ/Ϫ mice. Wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a ϩ/Ϫ mice. Thus partial HIF-1␣ deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.O xygen homeostasis is mediated by the combined physiologic functioning of the circulatory and respiratory systems. Recent studies have demonstrated that the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for both the establishment of the circulatory system during embryonic development and physiologic responses in postnatal life. Analysis of Hif1a Ϫ/Ϫ knockout mice, which are homozygous for a lossof-function mutation in the Hif1a gene encoding the O 2 -regulated HIF-1␣ subunit, revealed that complete HIF-1␣ deficiency results in embryonic lethality at midgestation with major malformations of the heart and vasculature (1-3). Hif1a ϩ/Ϫ heterozygous mice, which are partially HIF-1␣ deficient, develop normally and are indistinguishable from their wild-type littermates under normoxic conditions. However, adult Hif1a ϩ/Ϫ mice manifest impaired physiological responses to chronic hypoxia including significantly reduced rates of erythropoiesis and pulmonary vascular remodeling (4). Thus HIF-1␣ plays essential roles in cardiac, erythroid, and vascular development and physiology, i.e., all three major components of the circulatory system.An essential adaptation to both acute and chronic hypoxia is an increase in ventilation that depends on the activity of peripheral chemoreceptors, particularly those within the carotid body, which detect changes in arterial blood O 2 concentration and relay sensory information to the brainstem neurons that regulate breathing (reviewed in ref. 5). Altered ventilatory responses to hypoxia may play a critical role in asthma, diabetes, Parkinson's disease, sleep-related breathing disorders, and sudden infant death syndrome (6-8). We hypothesized that HIF-1␣ is required for carotid body function and ventilatory adaptation to chronic hypoxia. To test this hyp...

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“…This appears of particular interest because other authors reported that even an early stage of Parkinson's disease causes a subnormal response to hypoxia (43), and DJ-1, whose gene mutations lead to an inherited form of early-onset parkinsonism, is mainly involved in dopaminergic neuronal function in this pathology (11). Therefore, it would make sense to consider that DJ-1 may serve to protect not only cancer cells but also neuronal cells from hypoxia induced cell death.…”

Section: Discussionmentioning

confidence: 99%

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

Vasseur

Afzal

Tardivel-Lacombe

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

195

157

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In cancer, DJ-1/PARK7 acts as an oncogene that drives Akt-mediated cell survival. Although amplification of DJ-1 has been described in several types of tumors, the mechanistic basis of DJ-1's oncogenic effect remains incompletely understood. A tumor's ability to adapt to hypoxia is absolutely critical for its survival and progression, and this adaptation is largely mediated by the transcription factor HIF1. The stabilization of HIF1 subunits during hypoxia is at least partly dependent on the PI3K/Akt/mTOR pathway. We hypothesized that DJ-1, a positive regulator of Akt when over-expressed, might be involved in regulating HIF1 transcriptional activity under hypoxic conditions. Our results show that loss of DJ-1 in human cell lines and transformed mouse fibroblasts decreases the transcription of a variety of HIF1-responsive genes during hypoxia. Moreover, DJ-1 expression is critical for the Akt and mTOR activities that sustain HIF1 stability. Surprisingly, DJ-1 also regulates the activity of the metabolic sensor AMPK, especially during hypoxia. Finally, DJ-1 appears to protect cells against hypoxia-induced cell death and is required for their adaptation to severe hypoxic stress. Our work positions DJ-1 as an upstream activator of HIF1 function in cancer cells and establishes that DJ-1's oncogenic activity stems from its ability to increase a cell's resistance to hypoxic stress through DJ-1's regulatory effects on mTOR and AMPK. The discovery of these functions of DJ-1 strengthens the case for the development of therapeutics that target DJ-1 activity in cancer cells.mTOR ͉ AMPK ͉ apoptosis

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Impaired chemosensitivity and perception of dyspnoea in Parkinson's disease

Cited by 79 publications

References 5 publications

Neuroendocrine Functions of Melanocytes: Beyond the Skin-Deep Melanin Maker

Neuroendocrine Functions of Melanocytes: Beyond the Skin-Deep Melanin Maker

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

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