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

Monoclonal antibody (ML-30) directed against 65 kDa stress protein of mycobacteria, is shown to identify human cellular protein homologous with the groEL heat shock protein in many prokaryotes. Immunohistochemical survey of nervous tissue, both central and peripheral, from patients dying of various inflammatory, degenerative and neoplastic conditions and from experimental animals, using this antibody showed punctate granular staining of the cells to a variable degree. The astrocytes showed strong immunolabelling. The normal neurons and oligodendroglia stained variably, while abnormal neurons were darkly labelled. Ependymal cells showed apical granular positivity. The ubiquitinated inclusion bodies in amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease were not recognised by the ML-30 antibody. In diseased and stressed nervous tissue from experimental animals, the expression of the ML-30 recognisable stress protein was variable. The epitope recognised by ML-30 was found stable in postmortem tissues collected up to 36 h after death and processed for paraffin sectioning, after fixation in formalin for many years. Enhanced expression of the human groEL stress protein homologue in mammalian nervous tissue following various forms of stress may play a role in modulating the extent of tissue damage by autoimmune mechanism because of its high immunogenic nature and constitutive presence in the cells.
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PMID:Immunohistochemical study of the expression of human groEL-stress protein in human nervous tissue. 871 48

High-affinity N-methyl-D-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.
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PMID:Memantine induces heat shock protein HSP70 in the posterior cingulate cortex, retrosplenial cortex and dentate gyrus of rat brain. 897 91

It was suggested that neuronal degeneration in Parkinson's Disease (PD) is linked to dopamine (DA) toxicity. Dopamine has been shown to induce programmed cell death in both neuronal and non-neuronal cell types. We examined the molecular changes associated with dopamine-triggered apoptosis in sympathetic neurons using the differential display approach, and isolated 14 different DA responsive genes whose expression is altered during the early stages of the apoptotic process. Nine of these genes are upregulated and five are downregulated in response to DA exposure. Two of the upregulated genes were identified as cyclin B2 and a chicken homologue of chaperonin, a member of the heat shock protein family. Total increase in mRNA expression of both genes after 12 hours of exposure to DA was 40%. These two genes participate in cell cycle control and are specifically involved in determining entry of dividing cells into mitosis. Upregulation of mitosis-related genes in postmitotic sympathetic neurons undergoing apoptosis, may be indicative of an abortive attempt of these neurons to re-enter the cell cycle prior to their death. Possible implications to neuronal degeneration in PD are discussed.
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PMID:Induction of mitosis-related genes during dopamine-triggered apoptosis in sympathetic neurons. 912 Apr 26

Prion diseases such as Creutzfeldt-Jakob disease (CJD) are associated in most cases with the accumulation of an unusual isoform of prion protein (PrPSC). PrPSC is derived from the abnormal folding of the cellular isoform of prion protein (PrPC). On the other hand, heat shock protein is known to ensure proper protein assembly and folding and to facilitate proteolytic digestion of abnormal or denatured proteins. Many studies have therefore hypothesized that heat shock protein is linked to prion disease. We examined the relationship between heat shock protein HSP70 and prion disease in CJD patients. HSP70 mRNA levels in mononuclear blood cells (MBCs) were compared in 14 CJD patients (10 confirmed by histo-pathological study), 12 vascular dementia (VD) patients, 16 patients with Parkinson's disease and dementia (PD) and 14 nondemented control subjects. The possible correlation between HSP70 mRNA expression levels and clinical findings was also evaluated. HSP70 mRNA expression levels in MBCs were measured by northern blotting. HSP70 mRNA levels in MBCs from patients with CJD were significantly higher than those from patients with VD or PD and in nondemented controls. Age at symptom onset, dementia severity, disease duration and neuroimaging grade of CJD patients were not correlated with relative HSP70 mRNA levels. No significant relationship between HSP70 mRNA levels and ageing was found. These results suggest that measurement of HSP70 mRNA in MBCs might provide an auxiliary tool for the diagnosis of CJD.
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PMID:Creutzfeldt-Jakob disease: heat shock protein 70 mRNA levels in mononuclear blood cells and clinical study. 1120 Jun 84

TorsinA, a protein with homology to yeast heat shock protein104, has previously been demonstrated to colocalize with alpha-synuclein in Lewy bodies, the pathological hallmark of Parkinson's disease. Heat shock proteins are a family of chaperones that are both constitutively expressed and induced by stressors, and that serve essential functions for protein refolding and/or degradation. Here, we demonstrate that, like torsinA, specific molecular chaperone heat shock proteins colocalize with alpha-synuclein in Lewy bodies. In addition, using a cellular model of alpha-synuclein aggregation, we demonstrate that torsinA and specific heat shock protein molecular chaperones colocalize with alpha-synuclein immunopositive inclusions. Further, overexpression of torsinA and specific heat shock proteins suppress alpha-synuclein aggregation in this cellular model, whereas mutant torsinA has no effect. These data suggest that torsinA has chaperone-like activity and that the disease-associated GAG deletion mutant has a loss-of-function phenotype. Moreover, these data support a role for chaperone proteins, including torsinA and heat shock proteins, in cellular responses to neurodegenerative inclusions.
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PMID:TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation. 1242 56

Molecular chaperones and their functions in protein folding have been implicated in several neurodegenerative diseases, including Parkinson's disease and Huntington's disease, which are characterized by accumulation of protein aggregates (e.g., alpha-synuclein and huntingtin, respectively). These aggregates have been shown in various experimental systems to respond to changes in levels of molecular chaperones suggesting the possibility of therapeutic intervention and a role for chaperones in disease pathogenesis. It remains unclear whether chaperones also play a role in Alzheimer's disease, a neurodegenerative disorder characterized by beta-amyloid and tau protein aggregates. Here, we report an inverse relationship between aggregated tau and the levels of heat shock protein (Hsp)7090 in tau transgenic mouse and Alzheimer's disease brains. In various cellular models, increased levels of Hsp70 and Hsp90 promote tau solubility and tau binding to microtubules, reduce insoluble tau and cause reduced tau phosphorylation. Conversely, lowered levels of Hsp70 and Hsp90 result in the opposite effects. We have also demonstrated a direct association of the chaperones with tau proteins. Our results suggest that up-regulation of molecular chaperones may suppress formation of neurofibrillary tangles by partitioning tau into a productive folding pathway and thereby preventing tau aggregation.
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PMID:Chaperones increase association of tau protein with microtubules. 1252 69

The yeast gene YDR533C encodes a protein belonging to the DJ-1/ThiJ/PfpI superfamily. This family includes the human protein DJ-1, which is mutated in autosomal recessive early-onset Parkinson's disease. The function of DJ-1 and its yeast homologue YDR533Cp is unknown. We report here the crystal structure of YDR533Cp at 1.8-A resolution. The structure indicates that the closest relative to YDR533Cp is the Escherichia coli heat shock protein Hsp31 (YedU), which has both chaperone and protease activity. As expected, the overall fold of the core domain of YDR533Cp is also similar to that of DJ-1 and the bacterial protease PfpI. YDR533Cp contains a possible catalytic triad analogous to that of Hsp31 and an additional domain that is present in Hsp31 but is not seen in DJ-1 and other members of the family. The cysteine in this triad (Cys-138) is oxidized in this crystal structure, similar to modifications seen in the corresponding cysteine in the crystal structure of DJ-1. YDR533Cp appears to be a dimer both in solution and the crystal, but this dimer is formed by a different interface than that found in Hsp31 or other members of the superfamily.
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PMID:The 1.8-A resolution crystal structure of YDR533Cp from Saccharomyces cerevisiae: a member of the DJ-1/ThiJ/PfpI superfamily. 1474 11

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

Parkinson's disease (PD) is a neurodegenerative disorder affecting an estimated 4 million people worldwide. Intracellular proteinaceous inclusions called Lewy bodies are the histological hallmarks of PD and are primarily composed of aggregated alpha-synuclein (alphaSyn). Although the detailed mechanisms remain unclear, mounting evidence suggests that the misfolding of alphaSyn into prefibrillar and fibrillar species is the driving force responsible for cellular toxicity. We show here that the molecular chaperone heat shock protein (Hsp) 70 strongly inhibits alphaSyn fibril formation via preferential binding to prefibrillar species. Moreover, our studies reveal that Hsp70 alters the characteristics of toxic alphaSyn aggregates and indicate that cellular toxicity arises from the prefibrillar forms of alphaSyn. This work therefore elucidates a specific role of Hsp70 in the pathogenesis of PD and supports the general concept that chaperone action is a crucial aspect in protecting against the otherwise damaging consequences of protein misfolding.
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PMID:Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. 1567 Oct 22

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.
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PMID:Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia. 1589 10


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