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Volume 124 (2004)
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Volume 124, Issue 6
Displaying 1-8 of 8 articles from this issue
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Reviews: Topics on the Mechanism of ER Stress Involvement in the Regulation of Brain Cell Death
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—The pathogenetic mechanisms underlying AR-JP—Ryosuke TAKAHASHI2004 Volume 124 Issue 6 Pages 375-382
Published: 2004
Released on J-STAGE: November 26, 2004
JOURNAL FREE ACCESSMutations of the Parkin gene are responsible for autosomal recessive juvenile parkinsonism (AR-JP), the most common cause of early-onset familial Parkinson's disease. Parkin functions as an E3 ubiquitin ligase, thereby promoting ubiquitination and subsequent proteosomal degradation of its substrate(s). AR-JP is, therefore, thought to be caused by accumulation of an unknown toxic protein(s), which would normally be degraded by a molecular machinery involving Parkin. To date, ten different proteins are reported to be substrates of Parkin. Among these, a G protein-coupled orphan receptor called the Pael receptor (Pael-R), which is highly expressed in dopaminergic neurons, attracts particular attention. When over-expressed in cells, the Pael-R protein became improperly folded and insoluble. Excessive accumulation of insoluble Pael-R led to endoplasmic reticulum (ER) stress-induced cell death. Parkin was observed to ubiquitinate the misfolded Pael-R protein, thereby promoting its degradation and suppressing misfolded Pael-R-induced cell death. Moreover, selective dopaminergic neurodegeneration was observed when human Pael-R was ectopically expressed in Drosophila brain, further supporting the idea that Pael-R accumulation plays a major role in AR-JP. In contrast, neither dopaminergic neurodegeneration nor accumulation of any known Parkin substrates was detected in Parkin knockout mice. The role of Pael-R in AR-JP will be discussed based on recent data.
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a transmembrane bZIP transcription factor, in astrocytesKazunori IMAIZUMI, Masaya TOHYAMA2004 Volume 124 Issue 6 Pages 383-390
Published: 2004
Released on J-STAGE: November 26, 2004
JOURNAL FREE ACCESSThe endoplasmic reticulum (ER) is susceptible to various stresses that provoke the accumulation of unfolded proteins in the ER. Excessive or long-termed stresses in the ER result in apoptotic cell death involving activation of caspase-12 and -3 and the Ask-1-JNK pathway. Eukaryotic cells can adapt for survival to deal with an accumulation of unfolded proteins in the ER by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP to facilitate protein folding. The induction system is termed the unfolded protein response (UPR). It has been reported that IRE1 and PERK, transmembrane kinases, and ATF6, a transmembrane transcription factor, are mediators of the UPR through sensing accumulation of unfolded proteins. Cell fates after ER stress are regulated by the balance of both apoptotis and the UPR signaling. In the nervous systems, astrocytes are well known to be resistant to ER stresses induced by ischemia and hypoxia. These findings raise the possibility that astrocytes possess a novel UPR signaling different from that of neuronal cells. Recently, we identified a novel ER stress sensor, OASIS, which is specifically expressed in astrocytes. This protein is a transmembrane protein containing the bZIP domain. The functional analyses of OASIS showed that 1) it was cleaved within the ER membrane in response to the ER stress, 2) overexpression of OASIS induced the transcription of GRP78/BiP mRNA through the activation of cyclic AMP responsive element (CRE) and ER stress responsive element (ERSE), and 3) its stable cell lines were resistant to ER stress compared with the control cells. These results indicate that the ER-resident transcription factor OASIS may be a candidate for leading astrocytes to protect against ER stress.
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Masayuki KANEKO, Yasuyuki NOMURA2004 Volume 124 Issue 6 Pages 391-398
Published: 2004
Released on J-STAGE: November 26, 2004
JOURNAL FREE ACCESSEndoplasmic reticulum-associated degradation (ERAD) is a system in which unfolded proteins drained from the ER lumen to the cytosol are ubiquitinated then degraded by 26S proteasome. We have identified and characterized human HRD1 as a ubiquitin ligase involved in ERAD that protects against ER stress-induced cell death. Accumulation of Pael receptor (Pael-R), a substrate of Parkin, has been proposed to lead to neuronal death in Autosomal Recessive Juvenile Parkinsonism (AR-JP). HRD1 co-localized with Pael-R in the ER and interacted with Pael-R through the proline-rich region of HRD1. HRD1 ubiquitinated and degraded Pael-R through its ubiqutin ligase activity. Furthermore, we found that ATF6 and XBP1 that induce HRD1 promoted the degradation of Pael-R. A class of compounds known as chemical chaperones, such as 4-phenylbutyric acid (4-PBA), has been demonstrated to repair unfolded proteins. We demonstrated that 4-PBA protected against ER stress-induced neuronal cell death. The tunicamycin-induced up-regulation of GRP78 and GRP94 and phosphorylation of PERK was suppressed by treatment with 4-PBA, indicating that 4-PBA suppresses ER stress responses by decreasing unfolded protein. Furthermore, 4-PBA suppressed ER stress induced by the overexpression of Pael-R. Thus, up-regulation of HRD1 and 4-PBA could decrease accumulation of Pael-R.
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Kohichi KAWAHARA, Masataka MORI, Hitoshi NAKAYAMA2004 Volume 124 Issue 6 Pages 399-406
Published: 2004
Released on J-STAGE: November 26, 2004
JOURNAL FREE ACCESSNitric Oxide (NO) produced by activated microglia is an important contributor to neuronal damage. NO toxicity is generally thought to be mediated by the DNA damage-p53 pathway or mitochondrial dysfunction. We investigated the mechanism of NO toxicity by using microglial MG5 cells established from p53-deficient mouse. When MG5 cells were exposed to LPS plus IFN-γ, mRNA and protein for inducible NO synthase (iNOS) were markedly induced and apoptosis occurred. Under these conditions, we found that mRNA and protein for CHOP/GADD153, a C/EBP family transcription factor that is involved in ER stress-induced apoptosis, were induced. These results suggest that NO-induced apoptosis in MG5 cells occurs through the ER stress pathway involving CHOP, but is independent of p53. Overactivation-induced apoptosis may be an essential self-regulatory mechanism for microglia in order to limit bystander killing of vulnerable neurons. On the other hand, recent reports suggest that there may exist two subtypes of microglia at least in the CNS. We found activated rat type-1 microglia induced expression of iNOS and exhibited neurotoxic to rat hippocampal neurons. By contrast, activated type-2 microglia hardly exhibited neurotoxicity in this co-culture system. These results suggest that the two subtype(s) of microglia may regulate differently the inflammatory response in the CNS.
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Yoshihisa KITAMURA, Kazuyuki TAKATA, Takashi TANIGUCHI2004 Volume 124 Issue 6 Pages 407-413
Published: 2004
Released on J-STAGE: November 26, 2004
JOURNAL FREE ACCESSRecent studies have indicated that prolonged dysfunction and/or stress in the endoplasmic reticulum (ER) may contribute to pathogenesis and neurodegeneration. The disorder caused by misfolding and aggregation of proteins has been referred to as conformational disease, including Alzheimer's disease (AD). AD is characterized by the accumulation of extracellular amyloid-β1-42 (Aβ42) fibrils with reactive microglia. Understanding the balance of production and clearance of Aβ42 is the key to elucidating amyloid plaque homeostasis. We have recently found that microglial phagocytosis of Aβ42 may be essentially driven by dynamic reorganization of the actin cytoskeleton through the pathway of WAVE and Rac1. In addition, an extracellular stress protein, such as Hsp90, enhances Aβ42 phagocytosis. HMGB1 inhibits microglial phagocytosis of Aβ42, and it binds Aβ42 and stabilizes the oligomerization. These results suggest that microglial clearance of Aβ42 may be another option for investigations in the search for a therapeutic strategy for AD, in addition to the study of production and degradation of Aβ42.
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Review
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Masayoshi ABE, Tanihiro YOSHIMOTO2004 Volume 124 Issue 6 Pages 415-425
Published: 2004
Released on J-STAGE: November 26, 2004
JOURNAL FREE ACCESSThe first drugs affecting the leukotriene-lipoxygenase pathway, which have been introduced in clinical application, inhibit effects of slow reacting substance of anaphylaxis (SRS-A). Although, a 5-lipoxygenase inhibitor was first used in clinical practice as an anti-asthma drug, cysteinyl-leukotriene type 1 receptor (cysLT1R) antagonists are preferred as anti-asthma and anti-rhinitis drugs because they are almost as effective as the 5-lipoxygenase inhibitors but have fewer side effects. The cloning of genes related to lipoxygenase-leukotriene metabolism prompted us to try to elucidate the role of leukotrienes in various inflammations. There are at least two types of cysLTRs known: cysLT1R and cysLT2R. CysLT1R plays an important role in the pathophysiology of asthma; however, the role of the cysLT2R remains unknown. The abundant distribution of cysLT2R in heart and brain tissues suggests that cysLTs play an important role in the pathophysiology of ischemic heart diseases or arrhythmias and through this receptor (cysLT2R), psychoneurological disorders. The use of a selective cysLT2R antagonist may clarify these questions. Since the 5-lipoxygenase pathway is abundantly expressed in atherosclerotic lesions, and 12/15-lipoxygenase is able to oxygenate polyunsaturated fatty acid esterified in the membranous phospholipids, 5-lipoxygenase or 12/15-lipoxygenase inhibitors may prevent progression of atherosclerosis. In addition, it has been reported that 15-lipoxygenase participates in suppression of prostate cancer. In conclusion, the leukotriene-lipoxygenase metabolism may be involved in the pathophysiology of acute inflammatory to chronic progressive disorders. We think that more drugs modifying leukotriene-lipoxygenase metabolism will be introduced into clinical practice in the future.
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Akio NAKAMURA, Akira IMAIZUMI, Yukishige YANAGAWA2004 Volume 124 Issue 6 Pages 427-434
Published: 2004
Released on J-STAGE: November 26, 2004
JOURNAL FREE ACCESSThe majority of β2-adrenoceptor (β2-AR) agonists is eliminated via the kidneys as an unchanged substance. It is likely that such agents will exert pharmacological effects during their passage through the nephron. However, these pharmacological effects have, to our knowledge, not been taken into consideration when using these compounds in clinical practice because the role of β2-AR in the regulation of renal function remains unclear. Renal β2-ARs are predominantly localized to the proximal tubular epithelia and the membranes of smooth muscle cells from renal arteries. From this morphologic evidence, it is proposed that β2-AR activation may regulate glomerular function and thereby sodium and water balance in the nephron segments. Actually, β2-AR agonists given acutely cause a marked decrease in glomerular filtration rate. On the other hand, β2-AR agonists inhibit the renal production of inflammatory cytokines such as TNF-α. Furthermore, the administration of β2-AR agonists is found to attenuate apoptosis associated with shigatoxin in the hemolytic uremic syndrome (HUS). Increased understanding of the pharmacological basis of β2-AR function in the kidney provides important new information relevant to the clinical use of β2-AR agonists in airway diseases and potential applications of these drugs in renal inflammation and injury associated with sepsis or HUS.
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Review on New Drug
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Jiro ARITA, Tomoko OKUYAMA2004 Volume 124 Issue 6 Pages 435-444
Published: 2004
Released on J-STAGE: November 26, 2004
JOURNAL FREE ACCESSAge-related macular degeneration (AMD) is the leading cause of blindness among people aged over 50 years in the western world. Verteporfin (Visudyne®) is the first light-activated drug indicated for the treatment of patients with AMD caused by subfoveal choroidal neovascularization (CNV). This form of AMD is characterized by the development of abnormal blood vessels on the back of the retina that leak and cause scarring, resulting in central vision loss. Following intravenous administration, verteporfin selectively accumulates within proliferating tissue, including neovasculature, probably via low density lipoprotein receptors. The verteporfin is then activated by shining a specific wavelength of light with a nonthermal laser on the affected area in the eye. This process, called photodynamic therapy (PDT), generates reactive free radicals and highly reactive singlet oxygen in the target cells in the eye, causing damage and occlusion of the CNV and resulting in closure of the abnormal vessels and cessation of leakage. In experimentally induced CNV in animal models and in randomized, controlled clinical trials of patients with CNV due to AMD, verteporfin PDT has been shown to selectively occlude abnormal vessels without significantly altering overlying photoreceptors. Verteporfin therapy for CNV in Japanese patients had a similar or better angiographic and vision effect as that observed in Caucasian patients, with the same safety profile.
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