Coexistence of expanded CAG repeats in the MJD1a and DRPLA genes.
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Ataxin-3↗
Biomedical subjects
S Shimohama
Publications and source records attributed to S Shimohama.
p75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures.
Accumulating evidence suggests that the neurotrophin receptors, Trks and p75, play distinct roles in regulating cells survival and death, with Trks important for cell survival, and p75 acting to induce cell death. Here, we provide evidence that, in neuronal cultures from rat cerebral cortex, nerve growth factor (NGF) exerts neuroprotective actions via p75. Incubating cultures with NGF for 1-24 h protected cortical neurons from delayed cytotoxicity induced by brief exposure to glutamate. Delayed neurotoxicity induced by a calcium ionophore, ionomycin, or nitric oxide (NO) donors such as S-nitrosocysteine (SNOC) and 3-morpholinosydnonimine (SIN-1), was also attenuated by pretreatment with NGF. RT-PCR analysis revealed the presence of p75 and trkB transcripts in cortical cultures, but did not detect transcripts of trkA, a high-affinity receptor for NGF. Brain-derived neurotrophic factor (BDNF), but not NGF, induced tyrosine phosphorylation of Trks, indicating that NGF does not activate Trks in cortical neurons. Concurrent application of anti-p75 neutralizing antibody markedly reduced the neuroprotective effect of NGF, but resulted in only a modest reduction of that of BDNF. BDNF-induced neuroprotection, but not NGF-induced neuroprotection, was inhibited by a protein synthesis inhibitor cycloheximide. Distinct signaling pathways mobilized by NGF and BDNF were also revealed in that NGF but not BDNF stimulated significant production of ceramides, whereas BDNF but not NGF caused persistent activation of mitogen-activated protein kinases. These results indicate that, although NGF and BDNF both protect cortical neurons from excitotoxicity, the mechanisms involved in their effects are totally different. The present results are, to our knowledge, the first to demonstrate the principal involvement of p75 in cytoprotective actions of neurotrophins.
Animals↗
Neuroprotective effects of estradiol in mesencephalic dopaminergic neurons.
There is a gender difference, or male predominance, in Parkinson's disease and attention deficit hyperactivity disorder (ADHD). Although the reason why it is predominantly the male who suffers from the diseases is still unknown, the female steroid hormone may be involved in the pathogenesis. Estrogen is a female sex hormone with a steroid structure. Like other steroid hormones, it binds to specific receptors in the nuclei and regulates gene transcription (genomic effects). In addition to the genomic effects, it can act as an antioxidant, a process not mediated by the estrogen receptor (nongenomic effects). Further, estrogen can have a novel action through a specific receptor located in the plasma membrane. In the central nervous system, estrogen provides neuroprotection mediated through multiple mechanisms. In this article, we review several possible mechanisms for the neuroprotective effects including antiapoptotic protection by estrogens as transcription factors, protection against oxidative stress by estrogens acting as antioxidants, and neurotrophic cross talk through the signal cascade shared with neurotrophic factors.
Animals↗
Apoptosis in Alzheimer's disease--an update.
Alzheimer's disease (AD) is the most common human neurodegenerative disorder characterized by the progressive deterioration of cognition and memory in association with the presence of senile plaques, neurofibrillary tangles, and massive loss of neurons. Most cases of AD are late-onset and sporadic, but in some cases the disease is inherited as an autosomal dominant trait. Four different genes, the amyloid precursor protein, apolipoprotein E, and presenilins 1 and 2 have been implicated in the etiology of familial AD. It is now generally accepted that massive neuronal death due to apoptosis is a commmon characteristic in the brains of patients suffering from neurodegenerative diseases, and apoptotic cell death has been found in neurons and glial cells in AD. This review summarizes the current findings regarding the evidence for apoptosis in AD and discusses the possible involvement of apoptosis-regulating factors in the pathology of AD. Modification of the apoptotic cascade could be considered as a primary therapeutic strategy for the disease.
Alzheimer Disease↗
Neuroprotective mechanism of glial cell line-derived neurotrophic factor in mesencephalic neurons.
Glial cell line-derived neurotrophic factor (GDNF) provides neuroprotection, but its neuroprotective mechanism has not been resolved. We investigated the neuroprotective mechanism of GDNF using primary culture of the rat mesencephalon. Bleomycin sulfate (BLM) and L-buthionine-[S,R]-sulfoximine (BSO) caused apoptosis in both dopaminergic and nondopaminergic neurons, as revealed by the presence of chromatin condensation, and positive staining by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL). GDNF preincubation blocked the neurotoxicity and reduced the number of the TUNEL-positive cells caused by BLM and BSO exposure. In contrast, GDNF did not provide neuroprotection against glutamate toxicity, which was not accompanied by these apoptotic features. The neuroprotection was mediated by phosphatidylinositol 3-kinase, an effector downstream from c-Ret, because it was blocked by LY294002. GDNF pretreatment caused up-regulation of Bcl-2 and Bcl-x. Furthermore, GDNF suppressed oxygen radical accumulation caused by BLM. Apoptosis induced by BLM and BSO was blocked by a caspase-3 inhibitor. Caspase-3 activity was elevated by BLM and suppressed by GDNF pretreatment. These findings indicate that GDNF has no effect on necrosis but exerts protection against apoptosis by activation of phosphatidylinositol 3-kinase and the subsequent up-regulation of Bcl-2 and Bcl-x, which suppresses accumulation of oxygen radicals followed by caspase-3 activation.
Animals↗
Protein disulfide isomerase in Alzheimer disease.
There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.
Adolescent↗
Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons.
Parkinson's disease is characterized by the mesencephalic dopaminergic neuronal loss, possibly by apoptosis, and the prevalence is higher in males than in females. The estrogen receptor (ER) subtype in the mesencephalon is exclusively ER beta, a recently cloned novel subtype. Bound with estradiol, it enhances gene transcription through the estrogen response element (ERE) or inhibits it through the activator protein-1 (AP-1) site. We demonstrated that 17beta-estradiol provided protection against nigral neuronal apoptosis caused by exposure to either bleomycin sulfate (BLM) or buthionine sulfoximine (BSO). BLM and BSO-induced nigral apoptosis was blocked by inhibitors for caspase-3 or c-Jun/AP-1. The antiapoptotic effect by estradiol was blocked by ICI 182,780, an antagonist for ER, but not by a synthesized peptide that inhibits binding of the ER to the ERE. Estradiol had no effects on caspase-3 activation and c-Jun NH(2)-terminal kinase (JNK), which were activated by BLM. It also suppressed apoptosis by serum deprivation, which was independent of caspase-3 activation. Therefore, the antiapoptotic neuroprotection by estradiol is mediated by transcription through AP-1 site downstream from JNK and caspase-3 activation. Furthermore, 17alpha-estradiol, a stereoisomer without female hormone activity, also provided an antiapoptotic effect. Therefore, the antiapoptotic effect is independent of female hormone activity.
Animals↗
The parkinsonian models: invertebrates to mammals.
In contrast to Alzheimer's disease, effective therapeutic options are available for Parkinson's disease. Therapy of dopamine replacement such as levodopa improves the symptoms of this disease, but does not inhibit neurodegeneration in the substantia nigra. Numerous studies have suggested that endogenous and environmental neurotoxins, and oxidative stress may participate in this disease, but the detailed mechanisms are still unclear. Recent genetic studies in familial Parkinson's disease and parkinsonism show several gene mutations. This new information regarding pathogenesis offers novel prospects for therapy. To develop novel neuroprotective drugs, it is necessary to have a model for each type of parkinsonism. This review summarizes current findings regarding parkinsonian models in vertebrates and invertebrates and discusses their value.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
[Changes in apoptosis-regulating proteins in Alzheimer's disease: comparison with development and aging].
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Aging↗
Differential expression of small heat shock proteins in reactive astrocytes after focal ischemia: possible role of beta-adrenergic receptor.
Small heat shock proteins (sHSPs), a family of HSPs, are known to accumulate in the CNS, mainly in astrocytes, in several pathological conditions such as Alexander's disease, Alzheimer's disease, and Creutzfeldt-Jakob disease. sHSPs may act not only as molecular chaperones, protecting against various stress stimuli, but may also play a physiological role in regulating cell differentiation and proliferation. In the present study, we have demonstrated that transient focal ischemia in rats dramatically induced HSP27 but not alpha B-crystallin (alphaBC), both of which are members of sHSPs, in reactive astrocytes. In contrast, in vitro chemical ischemic stress induced both HSP27 and alphaBC in cultured glial cells to the same extent. Dibutyryl cAMP (dBcAMP) and isoproterenol, a beta-adrenergic receptor (betaAR) agonist, enhanced HSP27 expression but suppressed alphaBC, and changed the shape of the cells to a stellate form. dBcAMP and isoproterenol inhibited cell proliferation under normal conditions. An increase in betaAR-like immunoreactivity was also observed in reactive astrocytes in vivo. These results, together with recent findings that betaAR plays an important role in glial scar formation in vivo, raise the possibility that betaAR activation modulates sHSP expression after focal ischemia and is involved in the transformation of astrocytes to their reactive form.
Animals↗
Analysis of brain proteins in Alzheimer's disease using high-resolution two-dimensional gel electrophoresis.
Two-dimensional gel electrophoresis (2-DE), a method which can be used to analyze the expression of many proteins, is a promising and powerful approach which we have begun to use in the characterization of the complex pathologic processes in Alzheimer's disease (AD). In the present study, a reliable 2-DE database of human brain proteins was created by improving the reproducibility of 2-DE images using an immobilized pH gradient (IPG) for the first dimension gel electrophoresis and Melanie II as the program for data analysis. The brain samples were taken from the temporal cortex of brains at autopsy from 15 AD patients and 15 age-matched controls with non-neurological disorders. About 700 spots were located as consistently expressed proteins in the human brain, all of which were expressed also in AD brains. Comparing the density of spots between AD and normal control, we found that five protein spots were significantly increased, 28 spots were significantly decreased and nine spots were detected only in AD. Two spots among those significantly increased and one spot among those significantly decreased were identified as glial fibrillary acidic proteins. The database of brain proteins in AD constructed for the present study, including the statistical data of density changes in AD, should be a useful beginning for a comprehensive human 2-DE database available via the Internet, which will facilitate further investigation of pathogenic protein alterations in AD.
Aged↗
Requirement for mitogen-activated protein kinase in cerebellar long term depression.
The mitogen-activated protein kinase (MAPK) cascade has been shown to play an essential role in regulation of cell proliferation and cell differentiation. Although mammalian MAPKs are most abundantly expressed in postmitotic and terminally differentiated neuronal cells, their function in the central nervous system is still largely undefined. We present evidence here for a role of the MAPK cascade in cerebellar long term depression (LTD), which is a widely studied form of synaptic plasticity in mammalian brain. In cultured Purkinje cells, LTD is known to be induced by iontophoretic application of glutamate and depolarization of Purkinje cells. We found that MAPK was activated in Purkinje cells by treatment of primary cultures of rat embryonic cerebella with glutamate and a depolarization-inducing agent, KCl. Application of PD98059, a specific inhibitor of MAPK kinase (MAPKK/MEK), inhibited both the activation of MAPK and the induction of LTD in Purkinje cells. Furthermore, the induction of LTD was completely blocked by introduction into Purkinje cells of anti-active MAPK antibody, which was found to specifically and potently inhibit the activity of MAPK. These results suggest that postsynaptic activation of the MAPK cascade is essential for the induction of cerebellar LTD.
Animals↗
Changes in caspase expression in Alzheimer's disease: comparison with development and aging.
Changes in caspase-2 and -3 protein levels in Alzheimer's disease (AD) brains were assessed in comparison with their expression in development and aging. The protein levels of caspase-2 and -3 were significantly increased in AD brains, caspase-2 in the particulate fraction and caspase-3 in both the cytosolic and particulate fractions, compared with controls. Immunoblot analysis of brain extracts from embryonic day 19 (E19) to postnatal 96-week-old rats indicated that caspase-3 levels were high from E19 to 2 weeks, while caspase-2 remained high from 4 to 96 weeks, indicating that the expression of caspase-2 and -3 is differentially regulated during development and aging. These results suggest that caspase-2 and -3 are upregulated in AD and that the changes in AD are different from those observed in senescent brains.
Aged↗
Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's disease brains.
Recent studies suggest that inflammatory events are associated with plaque formation in the brains of patients with Alzheimer's disease (AD). Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) of these patients appears to slow the progression of disease. We assessed the occurrence of cyclooxygenases (COX-1 and -2) and peroxisome proliferator-activated receptor-gamma (PPARgamma) in temporal cortex from normal and AD brains using specific antibodies. In AD brains, protein levels of COX-1 were increased in both cytosolic and particulate fractions, and COX-2 protein was also increased in the particulate fraction. On the other hand, PPARgamma level was increased in the cytosolic fraction but not in the particulate fraction. Thus, expression levels of COX-1, COX-2, and PPARgamma may change in AD brains. In addition, several NSAIDs which are also PPARgamma activators, such as indomethacin, inhibited COX-2 expression in glial cells. These results suggest that PPARgamma activators have inhibitory effects on inflammatory events in AD brains.
Aged↗
Hydrogen peroxide-induced apoptosis mediated by p53 protein in glial cells.
It is now generally accepted that massive neuronal death due to oxidative stress is a regular feature of brains in neurodegenerative diseases. However, much less attention has been given to the death of glial cells. In this study, we examined p53-sensitive apoptosis of cells by using human glioblastoma A172 cells and p53-deficient mouse astrocytes. In human A172 cells, hydrogen peroxide (H2O2) caused cell death in a time- and concentration-dependent manner, accompanied by nucleosomal DNA fragmentation and chromatin condensation. After treatment with H2O2, p53 protein was highly expressed and protein levels of Bak, p21WAF1/CIP1 and GADD45 were also enhanced. However, the protein levels of Bcl-2 and Bax did not change. On the other hand, primary cultured astrocytes from p53-deficient mouse brain grew faster than wild-type and heterozygous astrocytes. In addition, p53-deficient astrocytes were more resistant to H2O2-induced apoptosis than wild-type and heterozygous astrocytes. These results suggest that glial proliferation and the repair of damaged DNA may be regulated by p53-induced p21WAF1/CIP1 and GADD45, and that glial apoptosis caused by oxidative stress may be mediated by p53-induced Bak.
Animals↗
Selective induction of glial glutamate transporter GLT-1 by hypertonic stress in C6 glioma cells.
Glial glutamate transporter GLT-1 mRNA was selectively induced in C6 glioma cells exposed to hypertonic stress (HS), while the expression of two other subtypes, GLAST and EAAC1, was suppressed. HS increased phosphorylation of the MAPK family, ERK, p38 MAPK, and JNK. Treatment with a PKC inhibitor showed that phosphorylation of both p38 MAPK and JNK is PKC-dependent but ERK phosphorylation is independent. Inhibition of either ERK or p38 MAPK did not abolish GLT-1 mRNA induction. Inhibition of PKC also had no effect. These findings indicate that the induction of GLT-1 mRNA by HS is independent of the MAPK pathways. This is the first report that the expression of glial glutamate transporters is osmotically regulated.
ATP-Binding Cassette Transporters↗
Depletion of intracellular glutathione increases susceptibility to nitric oxide in mesencephalic dopaminergic neurons.
Using primary neuronal cultures, we investigated the effects of GSH depletion on the cytotoxic effects of glutamate and NO in dopaminergic neurons. Intracellular GSH was depleted by 24-h exposure to L-buthionine-[S,R]-sulfoximine (BSO), an irreversible inhibitor of GSH synthase. BSO exposure caused concentration-dependent reduction of the viability of both dopaminergic and nondopaminergic neurons. In contrast, 24-h exposure of cultures to glutamate or NOC18, an NO-releasing agent, significantly reduced the viability of nondopaminergic neurons without affecting that of dopaminergic neurons. Pretreatment with N-acetyl-L-cysteine for 24 h ameliorated the NOC18-induced toxicity in nondopaminergic neurons. In dopaminergic neurons, sublethal concentrations of BSO reduced intracellular GSH content and markedly potentiated glutamate- and NOC18-induced toxicity. These results suggested that glutamate toxicity was enhanced in dopaminergic neurons by suppression of defense mechanisms against NO toxicity under conditions of GSH depletion. Under such conditions, free iron plays an important role because BSO-enhanced NO toxicity was ameliorated by the iron-chelating agent, deferoxamine. These results suggest that GSH plays an important role in the expression of NO-mediated glutamate cytotoxicity in dopaminergic neurons. Free iron may be related to enhanced NO cytotoxicity under GSH depletion.
Animals↗
The hydroxyl radical formation system in polymorphonuclear leukocytes.
We studied the hydroxyl radical (OH*)-generating system in polymorphonuclear leukocytes (PMNs). When phenylalanine was incubated with the alpha, beta and gamma fractions prepared from pig polymorphonuclear leukocytes (PMNs) and hydrogen peroxide (H2O2), significant levels of formation of m- and o-tyrosine were observed in the alpha and beta fractions, but not in the gamma fraction. The amount of tyrosine formation per milligram of protein was greater with the beta than with the alpha fraction. Further, when phenylalanine was incubated with alpha or beta fractions with similar myeloperoxidase (MPO) activities in the presence of H2O2, tyrosine formation by the beta fraction was also more effective. Using the beta fraction in which the MPO activity was destroyed by heat treatment, no significant amount of tyrosine was formed. However, with the heat-treated beta fraction and MPO preparations from human neutrophils in the presence of H2O2, the amount of tyrosine formation increased with the addition of increasing amounts of heat-treated beta fraction. Tyrosine formation by the beta fraction in the presence of H2O2 was significantly reduced by OH* scavengers. The above results suggest the existence of an OH*-generating system in which MPO and H2O2 participate in the granules of PMNs and, especially, in specific granules, there may exist some factors that cause more effective OH* generation.
Animals↗