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)

Genes associated with Parkinson's disease (PD) have suggested a role for ubiquitin-proteasome dysfunction and aberrant protein degradation in this disorder. Inasmuch as oxidative stress has also been implicated in PD, the present study examined transcriptional changes mediated by the Parkinsonism-inducing neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+) in a dopaminergic cell line. Microarray analysis of RNA isolated from toxin treated samples revealed that the stress-induced transcription factor CHOP/Gadd153 was dramatically up-regulated by both 6-OHDA and MPP+. Treatment with 6-OHDA also induced a large number of genes involved in endoplasmic reticulum stress and unfolded protein response (UPR) such as ER chaperones and elements of the ubiquitin-proteasome system. Reverse transcription-PCR, Western blotting, and immunocytochemical approaches were used to quantify and temporally order the UPR pathways involved in neurotoxin-induced cell death. 6-OHDA, but not MPP+, significantly increased hallmarks of UPR such as BiP, c-Jun, and processed Xbp1 mRNA. Both toxins increased the phosphorylation of UPR proteins, PERK and eIF2 alpha, but only 6-OHDA increased phosphorylation of c-Jun. Thus, 6-OHDA is capable of triggering multiple pathways associated with UPR, whereas MPP+ exhibits a more restricted response. The involvement of UPR in these widely used neurotoxin models supports the role of ubiquitin-proteasome pathway dysfunction in PD.
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PMID:Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. 1259 33

Parkin, the most commonly mutated gene in familial Parkinson's disease, encodes an E3 ubiquitin ligase. A number of candidate substrates have been identified for parkin ubiquitin ligase action including CDCrel-1, o-glycosylated alpha-synuclein, Pael-R, and synphilin-1. We now show that parkin promotes the ubiquitination and degradation of an expanded polyglutamine protein. Overexpression of parkin reduces aggregation and cytotoxicity of an expanded polyglutamine ataxin-3 fragment. Using a cellular proteasome indicator system based on a destabilized form of green fluorescent protein, we demonstrate that parkin reduces proteasome impairment and caspase-12 activation induced by an expanded polyglutamine protein. Parkin forms a complex with the expanded polyglutamine protein, heat shock protein 70 (Hsp70) and the proteasome, which may be important for the elimination of the expanded polyglutamine protein. Hsp70 enhances parkin binding and ubiquitination of expanded polyglutamine protein in vitro suggesting that Hsp70 may help to recruit misfolded proteins as substrates for parkin E3 ubiquitin ligase activity. We speculate that parkin may function to relieve endoplasmic reticulum stress by preserving proteasome activity in the presence of misfolded proteins. Loss of parkin function and the resulting proteasomal impairment may contribute to the accumulation of toxic aberrant proteins in neurodegenerative diseases including Parkinson's disease.
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PMID:Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. 1267 55

Mutations in the parkin gene cause the majority of cases of familial-linked Parkinson's disease, and mounting evidence suggests that parkin may play a role in idiopathic disease. Previous reports suggest that parkin may respond to and relieve, via E3-ligase activity, cellular stress at the endoplasmic reticulum caused by the accumulation of unfolded proteins. However, parkin's relationship to the mammalian unfolded protein response is unclear. Here, we comprehensively evaluate endogenous parkin in SH-SY5Y neuroblastomas at the promoter, RNA, and protein levels in response to unfolded protein stress induced by tunicamycin. While we find strong up-regulation of genes linked to the unfolded protein stress pathway, we detect no significant changes in parkin. These data suggest a lack of association between parkin and the unfolded protein response in SH-SY5Y cells.
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PMID:Parkin is not regulated by the unfolded protein response in human neuroblastoma cells. 1268 85

Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by mutations in the parkin gene. Parkin protein is characterized by a ubiquitin-like domain at its NH(2) terminus and by two RING finger motifs and one IBR (in between RING finger) motif at its COOH-terminus (RING-IBR-RING). We showed that the parkin protein is an E3 ubiquitin ligase, which binds to ubiquitin-conjugating enzymes (E2s) through its RING-IBR-RING motif. The pathogenesis of AR-JP, therefore, was hypothesized to be accumulation of unidentified neurotoxic protein (a substrate of parkin). On the basis of this hypothesis, the substrate of parkin was sought using a yeast two-hybrid system. A putative G protein-coupled transmembrane polypeptide, named Pael (parkin-associated endothelin receptor-like) receptor, was identified as a parkin binding protein. When overexpressed in cells, this receptor tends to become unfolded, insoluble, and ubiquitinated. The insoluble Pael receptor leads to endoplasmic reticulum (ER) stress-induced cell death. Parkin specifically ubiquitinates this receptor in the presence of ER-resident E2s and promotes the degradation of unfolded Pael receptor, resulting in suppression of the cell death induced by the accumulation of unfolded Pael receptor in the ER. Moreover, the insoluble form of Pael receptor accumulates in the brain of AR-JP patients. This protein is highly expressed in the dopaminergic neurons in the substantia nigra, which is specifically affected in Parkinson's disease; although it is also widely expressed in oligodendroglias in the fiber tract. In conclusion, we showed that the accumulation of unfolded Pael receptor (a substrate of parkin) may cause selective death of dopaminergic neurons in AR-JP.
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PMID:Parkin and endoplasmic reticulum stress. 1284 78

Various stresses cause the accumulation of unfolded proteins in the endoplasmic reticulum (ER). To manage the state, cells have the unfolded protein responses (UPR). If the UPR is unsuccessful, ER-mediated apoptosis occurs. To date, three types of UPR, i.e. the induction of chaperones, the translation block, and ER-associated degradation (ERAD) have been reported. To sense the accumulation of unfolded proteins, the ER has IRE1, PERK, and ATF6. The pathways mediated by IRE1 and ATF6 cause the induction of chaperones. The pathway mediated by PERK causes a translation block. The induction of caspase 12, the activation of the JNK pathway, and the induction of CHOP have been reported as apoptosis caused by ER stress. The stability of the cell is based on the balance between UPR and ER-mediated apoptosis. Recently several diseases have been reported to be related to ER stress. We reported that mutant presenilin 1 causes a vulnerability to ER stress because it attenuates the activation of IRE1, PERK, and ATF6. Recent reports have also shown that Parkinson disease and polyglutamine diseases are relevant to ER stress. Therefore it is suggested that the ER stress story is the common mechanism for neurodegerative disorders.
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PMID:[Involvement of unfolded protein responses in neurodegeneration]. 1288 50

Abnormal interactions and misfolding of synaptic proteins in the nervous system are being extensively explored as important pathogenic events resulting in neurodegeneration in various neurological disorders. These include Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). In AD, misfolded amyloid beta peptide 1-42 (Abeta), a proteolytic product of amyloid precursor protein metabolism, accumulates in the neuronal endoplasmic reticulum and extracellularly as plaques. In contrast, in PD and DLB cases there is abnormal accumulation of alpha-synuclein in neuronal cell bodies, axons, and synapses. Furthermore, in DLB, Abeta 1-42 may promote alpha-synuclein accumulation and neurodegeneration. The central event leading to synaptic and neuronal loss in these diseases is not completely clear yet; however, recent advances in the field suggest that nerve damage might result from the conversion of nontoxic monomers to toxic oligomers and protofibrils. The mechanisms by which misfolded Abeta peptide and alpha-synuclein might lead to synapse loss are currently under investigation. Several lines of evidence support the possibility that Abeta peptide and alpha-synuclein might interact to cause mitochondrial and plasma membrane damage upon translocation of protofibrils to the membranes. Accumulation of Abeta and alpha-synuclein oligomers in the mitochondrial membrane might result in the release of cytochrome C with the subsequent activation of the apoptosis cascade. Conversely, the oxidative stress and mitochondrial dysfunction associated with AD and PD may also lead to increased membrane permeability and cytochrome C release, which promotes Abeta and alpha-synuclein oligomerization and neurodegeneration. Together, these studies suggest that the translocation of misfolded proteins to the mitochondrial membrane might play an important role in either triggering or perpetuating neurodegeneration. The insights obtained from the characterization of this process may be applied to the role of mitochondrial dysfunction in other neurodegenerative disorders, including AD. New evidence may also provide a rationale for the mitochondrial membrane as a target for therapy in a variety of neurodegenerative diseases.
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PMID:Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. 1452 50

Inhibition of mitochondrial function and the subsequent generation of oxidative stress are strongly suggested to underlie MPTP/MPP+-induced neurotoxicity, which has been used extensively as a model for Parkinson disease. In the present study we have examined the hypothesis that MPP+ targets the endoplasmic reticulum. Because rabbits possess more genetic similarities to primates than to rodents we have selected this animal model system for our MPP+ neurotoxicity studies. MPP+ was administered directly into the brain of New Zealand white rabbits via the intracisternal route, and the effects on tissue from the substantia nigra were examined. Here we demonstrate that MPP+ in a dose-dependent manner induces the loss of tyrosine hydroxylase activity, oxidative DNA damage, and activation of the endoplasmic reticulum stress response. The endoplasmic reticulum response, mediated by activation of ATF-6 and NF-kappaB, leads to activation of gadd 153. These effects correlate with the activation of caspase-3 and of c-Jun N-terminal kinase (JNK) kinase. We propose that pharmacological agents that inhibit the perturbation of endoplasmic reticulum function or the activation of JNK may represent a potential therapeutic approach for the prevention of neurotoxin-induced Parkinson disease.
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PMID:MPP+ induces the endoplasmic reticulum stress response in rabbit brain involving activation of the ATF-6 and NF-kappaB signaling pathways. 1465 72

The endoplasmic reticulum (ER) is a small intracellular organelle to which one-third of cellular proteins are translocated after translation and post-translational modification, folding and the formation of a three- or four-dimensional structure. ER also has a role in the transportation of proteins to other intracellular organelles, the cell surface or the outer space of the cell membrane. Thus, ER is an important intermediate which maintains intracellular homeostasis through complex control systems. Once these control systems are disrupted, serious disturbances occur. Many neurodegenerative diseases including Parkinson's disease involve aggregation and deposition of misfolded proteins such as alpha-synuclein. Endogenously occurring neurotoxins such as Salsolinol and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) causing Parkinsonism may foster misfolded proteins and bring forth ER stress in dopaminergic neurons. In the present study we examined translational changes fostered by ER stress and mediated by the Parkinsonian endogenous neurotoxins, salsolinol and 1BnTIQ, in dopaminergic cell line. Treatment with salsolinol and 1BnTIQ induced several genes involved in ER stress and unfolded protein response (UPR), such as ER chaperones and GADD153 (CHOP). Immunoblotting confirmed phosphorylation of the key endoplasmic reticulum stress kinase PERK (PKR-like-ER kinase) and eIF2alpha and induction of their downstream targets such as Bip and GADD153. These findings suggest a widespread involvement of ER stress and unfolded protein response in the pathophysiology of Parkinson's disease.
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PMID:Salsolinol causing parkinsonism activates endoplasmic reticulum-stress signaling pathways in human dopaminergic SK-N-SH cells. 1473 62

Astrocytes, the most abundant glial cell types in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions can critically influence neuronal survival. Recent studies show that astrocyte apoptosis may contribute to pathogenesis of many acute and chronic neurodegenerative disorders, such as cerebral ischemia, Alzheimer's disease and Parkinson's disease. We found that incubation of cultured rat astrocytes in a Ca(2+)-containing medium after exposure to a Ca(2+)-free medium causes an increase in intracellular Ca(2+) concentration followed by apoptosis, and that NF-kappa B, reactive oxygen species, and enzymes such as calpain, xanthine oxidase, calcineurin and caspase-3 are involved in reperfusion-induced apoptosis. Furthermore, we demonstrated that heat shock protein, mitogen-activated protein/extracellular signal-regulated kinase, phosphatidylinositol-3 kinase and cyclic GMP phosphodiesterase are target molecules for anti-apoptotic drugs. This review summarizes (1) astrocytic functions in neuroprotection, (2) current evidence of astrocyte apoptosis in both in vitro and in vivo studies including its molecular pathways such as Ca(2+) overload, oxidative stress, NF-kappa B activation, mitochondrial dysfunction, endoplasmic reticulum stress, and protease activation, and (3) several drugs preventing astrocyte apoptosis. As a whole, this article provides new insights into the potential role of astrocytes as targets for neuroprotection. In addition, the advance in the knowledge of molecular mechanisms of astrocyte apoptosis may lead to the development of novel therapeutic strategies for neurodegenerative disorders.
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PMID:Astrocyte apoptosis: implications for neuroprotection. 1506 28

The causes of sporadic Parkinson's disease (PD) are poorly understood. 6-Hydroxydopamine (6-OHDA), a PD mimetic, is widely used to model this neurodegenerative disorder in vitro and in vivo; however, the underlying mechanisms remain incompletely elucidated. We demonstrate here that 6-OHDA evoked endoplasmic reticulum (ER) stress, which was characterized by an up-regulation in the expression of GRP78 and GADD153 (Chop), cleavage of procaspase-12, and phosphorylation of eukaryotic initiation factor-2 alpha in a human dopaminergic neuronal cell line (SH-SY5Y) and cultured rat cerebellar granule neurons (CGNs). Glycogen synthase kinase-3 beta (GSK3beta) responds to ER stress, and its activity is regulated by phosphorylation. 6-OHDA significantly inhibited phosphorylation of GSK3beta at Ser9, whereas it induced hyperphosphorylation of Tyr216 with little effect on GSK3beta expression in SH-SY5Y cells and PC12 cells (a rat dopamine cell line), as well as CGNs. Furthermore, 6-OHDA decreased the expression of cyclin D1, a substrate of GSK3beta, and dephosphorylated Akt, the upstream signaling component of GSK3beta. Protein phosphatase 2A (PP2A), an ER stress-responsive phosphatase, was involved in 6-OHDA-induced GSK3beta dephosphorylation (Ser9). Blocking GSK3beta activity by selective inhibitors (lithium, TDZD-8, and L803-mts) prevented 6-OHDA-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), DNA fragmentations and cell death. With a tetracycline (Tet)-controlled TrkB inducible system, we demonstrated that activation of TrkB in SH-SY5Y cells alleviated 6-OHDA-induced GSK3beta dephosphorylation (Ser9) and ameliorated 6-OHDA neurotoxicity. TrkB activation also protected CGNs against 6-OHDA-induced damage. Although antioxidants also offered neuroprotection, they had little effect on 6-OHDA-induced GSK3beta activation. These results suggest that GSK3beta is a critical intermediate in pro-apoptotic signaling cascades that are associated with neurodegenerative diseases, thus providing a potential target site amenable to pharmacological intervention.
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PMID:Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. 1513 87


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