Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genipin is an iridoid compound and an aglucon of geniposide isolated from Gardenia fructus. We have previously reported that genipin induces neurite outgrowth in PC12h and Neuro2a cells and protects against cytotoxicity induced by several conditions such as beta-amyloid peptide, serum deprivation, and oxidative stress in rat primary hippocampal neurons and Neuro2a cells. In this paper, we examined the protective effect of genipin on A23187 (a calcium ionophore)-induced cytotoxicity in Neuro2a cells. A23187 induced cytotoxicity in concentration- and time-dependent manners as assayed by measurements of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetazolium bromide (MTT) reduction activity and lactate dehydrogenase (LDH) release. The cytotoxicity was significantly suppressed by genipin in a concentration-dependent manner. A23187 also significantly activated caspase3/7, which is known to be the critical mediator of apoptosis, after 1 h, and the cytotoxicity was clearly blocked by an inhibitor of caspase 3/7. Furthermore, A23187 induced the expression of immunoglobulin-binding protein/glucose-regulated protein of 78 kDa (BiP/GRP78) protein, which is an endoplasmic reticulum (ER) stress marker protein, and the expression was suppressed by genipin. These results suggest that genipin protects Neuro2a cells from A23187-induced cytotoxicity mediated by caspase 3/7 and ER stress. Therefore, genipin may be effective in preventing neurodegeneration observed in Alzheimer's disease and Parkinson's disease involving ER stress.
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PMID:Genipin suppresses A23187-induced cytotoxicity in neuro2a cells. 1948 12

l-DOPA is the gold standard for the treatment of Parkinson's disease. Despite the obvious benefits of l-DOPA treatment, a potential drawback of such a treatment is its potential for neurotoxicity. The best-known potential mechanisms of l-DOPA toxicity involve oxidative stress, including nitrosative stress and increased generation of neurotoxins, oxidation of l-DOPA to quinone and semiquinone, mitochondrial dysfunction and genomic DNA damage. On the other hand, it has also been reported that l-DOPA is not neurotoxic, but rather neuroprotective. Although there are many studies on the neurotoxicity of l-DOPA, a debate regarding its effect on neuronal cells still remains. Glycogen synthase kinase-3 (GSK-3) affects a diverse range of biological functions controlling gene expression, cellular architecture and apoptosis. Recently, important roles of GSK-3 in l-DOPA neurotoxicity have been suggested by studies using an endoplasmic reticulum-stressed Parkinson's disease model. In this review, we focus our discussion on the following topics: i) l-DOPA neurotoxicity; ii) the role of GSK-3 in neuronal cell death; iii) the role of GSK-3 in l-DOPA neurotoxicity; and iv) the development of new GSK-3 inhibitors.
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PMID:Role of glycogen synthase kinase-3 in l-DOPA-induced neurotoxicity. 1966 31

Epidemiologic and laboratory studies suggest that paraquat can be an environmental etiologic factor in Parkinson's disease (PD). One mechanism by which paraquat may mediate cell death of dopaminergic neurons is by inducing endoplasmic reticulum (ER) stress, as suggested in a recent report. In this study, we further investigated this linkage by examining ER stress cascades. To this aim, human neuroblastoma cells (SH-SY5Y cells) were treated with paraquat and the signaling cascades through which ER stress results in apoptosis were examined. Then, it was examined whether ER stress is produced by paraquat. Paraquat increased ER stress biomarker proteins, glucose-regulated protein 78 (GRP78), ER degradation-enhancing alpha-mannosidae-like protein (EDEM), and C/EBP homologous protein (CHOP). Then, it was investigated which ER stress cascades are affected by paraquat. Paraquat activated inositol-requiring enzyme 1 (IRE1), apoptosis signal regulating kinase 1 (ASK1), and c-jun kinase (JNK). Also, paraquat activated calpain and caspase 3, but did not affect the levels of intracellular calcium and the activity of caspase 12. Finally, apoptotic DNA damage by paraquat was investigated and this damage was attenuated by salubrinal (ER stress inhibitor), thioredoxin (ASK1 inhibitor) and SP600125 (JNK inhibitor). Therefore, current data indicate that paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in SY5Y cells.
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PMID:Paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in human neuroblastoma SH-SY5Y cells. 1973 4

Anxiety is an instinct that may have developed to promote adaptive survival by evading unnecessary danger. However, excessive anxiety is disruptive and can be a basic disorder of other psychiatric diseases such as depression. The KF-1, a ubiquitin ligase located on the endoplasmic reticulum (ER), may prevent excessive anxiety; kf-1(-/-) mice exhibit selectively elevated anxiety-like behavior against light or heights. It is surmised that KF-1 degrades some target proteins, responsible for promoting anxiety, through the ER-associated degradation pathway, similar to Parkin in Parkinson's disease (PD). Parkin, another ER-ubiquitin ligase, prevents the degeneration of dopaminergic neurons by degrading the target proteins responsible for PD. Molecular phylogenetic studies have revealed that the prototype of kf-1 appeared in the very early phase of animal evolution but was lost, unlike parkin, in the lineage leading up to Drosophila. Therefore, kf-1(-/-) mice may be a powerful tool for elucidating the molecular mechanisms involved in emotional regulation, and for screening novel anxiolytic/antidepressant compounds.
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PMID:KF-1 Ubiquitin Ligase: An Anxiety Suppressor. 1975 93

Prion diseases are characterized by the conformational transition of the cellular prion protein (PrP(C)) into an aberrant protein conformer, designated scrapie-prion protein (PrP(Sc)). A causal link between protein misfolding and neurodegeneration has been established for a variety of neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease and polyglutamine diseases, but there is an ongoing debate about the nature of the neurotoxic species and how non-native conformers can damage neuronal populations. PrP is normally imported into the endoplasmic reticulum (ER) and targeted to the outer leaflet of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. However, several conditions, such as ER stress or some pathogenic mutations in the PrP gene, can induce the mislocalization of PrP in the cytosol, where it has a neurotoxic potential as demonstrated in cell culture and transgenic mouse models. In this review we focus on intrinsic factors and cellular pathways implicated in the import of PrP into the ER and its mistargeting to the cytosol. The findings summarized here not only reveal a complex regulation of the biogenesis of PrP, but also provide interesting new insight into toxic activities of pathogenic protein conformers and quality control pathways of ER-targeted proteins.
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PMID:Targeting of the prion protein to the cytosol: mechanisms and consequences. 1976 54

Various stresses, which impair ER (endoplasmic reticulum) function, lead to an accumulation of unfolded or misfolded proteins. ER stress triggers many rescuer responses, including a UPR (unfolded protein response). Increasing evidence has suggested that ER stress is involved in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and cerebral ischaemic insults), cancer, obesity and diabetes. In the present review, we consider the importance of ER stress under pathological conditions in mammals. Furthermore, we discuss the therapeutic potential for treatment targeting ER stress.
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PMID:Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. 1978 Jul 18

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies. Recently, many studies have focused on the interaction between alpha-synuclein and catecholamine in the pathogenesis of PD. However, no detailed relationship between cathecholamine and alpha-synuclein cytotoxicity has been elucidated. Therefore, this study established PC12 cell lines which overexpress human alpha-synuclein in a tetracycline-inducible manner. The overexpression of human alpha-synuclein increased the number of apoptotic cells in a long-term culture. Moreover, human alpha-synuclein expressing PC12 cells demonstrated an increased vulnerability to several stressors in a short culture period. Thapsigargin increased the SDS soluble oligomers of alpha-synuclein associated with catecholamine-quinone. The unfolded protein response (UPR) study showed that thapsigargin increased eIF2alpha phosphorylation and nuclear GADD153/CHOP induction under alpha-synuclein overexpressed conditions. The activities of the ATF6alpha and IRE1alpha pathways decreased. These findings suggest that an overexpression of alpha-synuclein partly inactivates the UPR. alpha-Methyltyrosine inhibited the dysfunction of the UPR caused by an overexpression of human alpha-synuclein. Therefore, these findings suggest that the coexistence of human alpha-synuclein with catecholamine enhances the endoplasmic reticulum stress-related toxicity in PD pathogenesis.
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PMID:Endogenous catecholamine enhances the dysfunction of unfolded protein response and alpha-synuclein oligomerization in PC12 cells overexpressing human alpha-synuclein. 1983 16

The clinical manifestation of most diseases of the central nervous system results from neuronal dysfunction or loss. Diseases such as stroke, epilepsy and neurodegeneration (e.g. Alzheimer's disease and Parkinson's disease) share common cellular and molecular mechanisms (e.g. oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction) that contribute to the loss of neuronal function. Neurotrophic factors (NTFs) are secreted proteins that regulate multiple aspects of neuronal development including neuronal maintenance, survival, axonal growth and synaptic plasticity. These properties of NTFs make them likely candidates for preventing neurodegeneration and promoting neuroregeneration. One approach to delivering NTFs to diseased cells is through viral vector-mediated gene delivery. Viral vectors are now routinely used as tools for studying gene function as well as developing gene-based therapies for a variety of diseases. Currently, many clinical trials using viral vectors in the nervous system are underway or completed, and seven of these trials involve NTFs for neurodegeneration. In this review, we discuss viral vector-mediated gene transfer of NTFs to treat neurodegenerative diseases of the central nervous system.
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PMID:Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS. 1984 Aug 53

alpha-Synuclein (alpha Syn) is the main component of Lewy bodies formed in midbrain dopaminergic neurons which is a pathological characteristic of Parkinson's disease. It has been recently showed to induce endoplasmic reticulum (ER) stress and impair ER functions. However, the mechanism of how ER responds to alpha Syn toxicity is poorly understood. In the present study, we found that protein disulfide isomerase (PDI), a stress protein abundant in ER, effectively inhibits alpha Syn fibril formation in vitro. In PDI molecule with a structure of abb'xa'c, domain a' was found to be essential and sufficient for PDI to inhibit alpha Syn fibril formation. PDI was further found to be more avid for binding with intermediate species formed during alpha Syn fibril formation, and the binding was more intensive in the later lag phase. Our results provide new insight into the role of PDI in protecting ER from the deleterious effects of misfolded protein accumulation in many neurodegenerative diseases.
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PMID:Domain a' of protein disulfide isomerase plays key role in inhibiting alpha-synuclein fibril formation. 1996 Feb 84

Increasing evidence has been suggested that hyperhomocysteinemia is a risk factor of neurodegenerative diseases, although, the underlying mechanisms have not been elucidated. Here, we found peripheral application of homocysteine increases X-box-binding protein 1 (XBP1) splicing in the several areas of the mice brain, such as hippocampus, hypothalamus and cortex. Time-course experiments indicated that XBP1 splicing was observed from 2h, which was decreased thereafter. On the other hand, we did not observe GRP78 or CHOP induction in homocysteine-treated mice brain. As XBP1 is spliced in response to endoplasmic reticulum (ER) stress and ER stress has been implicated in the pathogenesis of CNS diseases such as Alzheimer's disease and Parkinson's disease, homocysteine-induced XBP1 splicing would be a key mechanism for such diseases.
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PMID:Homocysteine induces X-box-binding protein 1 splicing in the mice brain. 2001 21


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