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)

Inflammatory reaction is thought to be an important contributor to neuronal damage in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and the parkinsonism dementia complex of Guam. Among the toxic agents released in brain tissues by activated cells, we focus attention in this review on peroxynitrite, the product of the reaction between nitric oxide (NO) and superoxide. Peroxynitrite is a strong oxidizing and nitrating agent which can react with all classes of biomolecules. In the CNS it can be generated by microglial cells activated by pro-inflammatory cytokines or beta-amyloid peptide (beta-A) and by neurons in three different situations: hyperactivity of glutamate neurotransmission, mitochondrial dysfunction and depletion of L-arginine or tetrahydrobiopterin. The first two situations correspond to cellular responses to an initial neuronal injury and the peroxynitrite formed only exacerbates the inflammatory process, whereas in the third situation the peroxynitrite generated directly contributes to the initiation of the neurodegenerative process.
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PMID:Neurodegenerative disorders: the role of peroxynitrite. 1052 72

Oxidative stress is a putative factor in the pathogenesis of many human disorders of the central nervous system. Therefore, antioxidants such as vitamin E have become attractive as therapeutic agents in the treatment of several diseases. In addition, vitamin E seems to play a specific role in the nervous system. As a result, vitamin E has been used in pharmacologic doses in the treatment of disorders such as Parkinson disease, Alzheimer disease, and tardive dyskinesia. One investigation showed that the use of 2000 IU all-rac-alpha-tocopheryl acetate is beneficial in the treatment of Alzheimer disease. Similar doses of vitamin E, however, were not beneficial for delaying the progression of Parkinson disease. In other studies, dosages >/=400 IU vitamin E/d were found to be beneficial in the treatment of tardive dyskinesia, although this finding was not confirmed in a larger cooperative study conducted by the Veterans Administration. Even though the efficacy of vitamin E in the management of cardiovascular disease has been shown, the potential role of vitamin E in the treatment of cerebrovascular disease remains essentially unknown. The experience from 2 large clinical trials involving the oral intake of 2000 IU vitamin E/d suggests that vitamin E is relatively safe at this dosage for periods <2 y. However, the safety and efficacy of supplemental vitamin E over periods of many years in the prevention of neurologic diseases has not been adequately explored.
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PMID:High doses of vitamin E in the treatment of disorders of the central nervous system in the aged. 1087 82

Programmed cell death or apoptosis is a widespread biological phenomenon. Apoptosis is characterized by typical cell features such as membrane blebbing, chromatin condensation, and DNA fragmentation. It involves a number of membrane receptors (e.g., Fas, TNFR) and a cascade of signal transduction steps resulting in the activation of a number of cysteine proteases known as caspases. Disordered apoptosis may lead to carcinogenesis and participates in the pathogenesis of Alzheimer disease, Parkinson disease, or AIDS. Programmed cell death plays an important role in the processes of gamete maturation as well as in embryo development, contributing to the appropriate formation of various organs and structures. Apoptosis is one of the mechanisms of action of various cytotoxic agents and teratogens. Teratogen-induced excessive death of embryonic cells is undoubtedly one of the most important events preceding the occurrence of structural abnormalities, regardless of their nature. Therefore understanding the mechanisms involved in physiological as well as in disturbed or dysregulated apoptosis may lead to the development of new methods of preventive treatment of various developmental abnormalities. The present review summarizes data on the mechanisms of programmed cell death and concentrates on apoptosis involved in normal or disturbed gametogenesis and in normal and abnormal embryonic development.
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PMID:The role of apoptosis in normal and abnormal embryonic development. 1057 78

Alzheimer disease appears to be a stereotyped mode of reaction of the central nervous system to various types of aggression such as different mutations involving various proteins, trisomy 21 or repeated head trauma as in dementia pugilistica. Rather than a disease, it appears to be a clinicopathological syndrome due to various causes. Lesions may be considered under 3 headings: neurofibrillary pathology, A beta peptide deposits and loss (neuronal and synaptic). Neurofibrillary pathology includes the neurofibrillary tangle, the crown of the senile plaque and the neuropil threads. All those lesions are characterized by the same ultrastructure--i.e. the accumulation of paired helical filaments--and the same immunohistochemistry: they are labelled by antibodies directed against the tau proteins. The amyloid deposits, present in the core of the senile plaque and in the vascular walls, are made of a 40 to 42 amino-acids long peptide, named A beta, derived from the amyloid precursor protein (APP). Antibodies directed against the A beta peptide also label diffuse deposits that are devoid of the tinctorial affinities and of the biochemical properties of amyloid substances. Those diffuse deposits are insufficient to cause dementia since they may be observed in high density in aged people without intellectual deterioration. Neuronal loss occurs after neurofibrillary pathology. The role of the synaptic pathology remains discussed. Besides tau proteins, A beta peptide and APP, several other proteins may play an important role: apolipoprotein E which could act as a chaperone protein, inducing or facilitating the formation of amyloid, presenilins 1 and 2, mutated in some cases of familial Alzheimer disease, alpha-synuclein which is present in the Lewy bodies found in Parkinson disease and in dementia with Lewy bodies. The A beta deposits are diffusely distributed in the cerebral cortex; the neurofibrillary changes have a hierarchical distribution. The progression of the neurofibrillary pathology in the various cortical areas follow a stereotyped sequence that may help to grade the severity of the disease. Progression may take decades. The relations between aging and Alzheimer disease are still poorly understood. Frequency of Alzheimer type lesions in old people could suggest that they are the inevitable burden of age, but this has been discussed.
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PMID:[Alzheimer's disease: lesions and their progression]. 1063 34

Synaptic degeneration and death of nerve cells are defining features of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most prevalent age-related neurodegenerative disorders. In AD, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable. In PD dopamine-producing neurons in the substantia nigra-striatum (brain regions that control body movements) selectively degenerate. Studies of postmortem brain tissue from AD and PD patients have provided evidence for increased levels of oxidative stress, mitochondrial dysfunction and impaired glucose uptake in vulnerable neuronal populations. Studies of animal and cell culture models of AD and PD suggest that increased levels of oxidative stress (membrane lipid peroxidation, in particular) may disrupt neuronal energy metabolism and ion homeostasis, by impairing the function of membrane ion-motive ATPases and glucose and glutamate transporters. Such oxidative and metabolic compromise may there-by render neurons vulnerable to excitotoxicity and apoptosis. Studies of the pathogenic mechanisms of AD-linked mutations in amyloid precursor protein (APP) and presenilins strongly support central roles for perturbed cellular calcium homeostasis and aberrant proteolytic processing of APP as pivotal events that lead to metabolic compromise in neurons. Specific molecular "players" in the neurodegenerative processes in AD and PD are being identified and include Par-4 and caspases (bad guys) and neurotrophic factors and stress proteins (good guys). Interestingly, while studies continue to elucidate cellular and molecular events occurring in the brain in AD and PD, recent data suggest that both AD and PD can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). Emerging evidence that dietary restriction can forestall the development of AD and PD is consistent with a major "metabolic" component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable.
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PMID:Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer's and Parkinson's diseases. 1067 36

Differential expression of the amyloid precursor protein gene (APP) may be important in the development of amyloidosis in Alzheimer's disease (AD) and experimentally in the brain's response to injury. Controversial data suggests that APP isoforms containing the Kunitz protease inhibitor isoform (APP KPI+) are over expressed in the brains of patients with AD when compared to the non-Kunitz protease inhibitor containing isoforms (APP KPI-). We have investigated this hypothesis using a quantitative analysis of gene expression on brain tissue collected at post-mortem. In situ hybridization has been used with synthetic oligonucleotide probes labelled with 35S to detect the two principal splice variants of APP: APP 695 (KPI-) and APP 751 (KPI+). A prospective brain bank of frozen brain specimens has been established and includes pathologically proven AD (n=15) and other neurodegenerative disorders as controls (n=18). The controls consist of frontal lobe atrophy (n=4), Huntington's disease (n=5), Parkinson's disease (n=4), motor neuron disease (n=2), multi-infarct dementia (n=1), multisystem atrophy (n=1), and subacute sclerosing panencephalitis (n=1). We have observed no significant differences in the expression of APP 695 KPI- mRNA in frontal lobe: 17.49+/-3.26 optical density (OD) units of mRNA expression in AD vs. 16.13+/-1.76 OD units mRNA in controls (P=0.80, linear regression); or temporal lobe: 14.73+/-2.96 in AD vs. 16.49+/-2.15 in controls (P=0.55). No significant differences have been found in APP 751 KPI+ in frontal lobe: 12.86+/-2.98 in AD vs. 13.70+/-2.88 in controls (P=0.97); and temporal lobe: 13.31+/-4.93 in AD vs. 11.07+/-1.99 in controls (P=0. 65). Analysis of the ratios of APP 751 KPI+ OD units of mRNA to APP 695 KPI- mRNA revealed a trend to an increased ratio which did not reach statistical significance: frontal lobe APP 751 KPI+/APP 695 KPI- 1.92+/-1.04 in AD vs. 0.86+/-0.17 in controls (P=0.54); temporal lobe 2.54+/-1.59 in AD vs. 0.96+/-0.11 controls (P=0.34). Our data has not revealed differential expression of APP mRNA isoforms in AD and supports the hypothesis that post-translational events in APP metabolism are important in amyloidogenesis and the pathogenesis of AD.
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PMID:Amyloid precursor protein gene isoforms in Alzheimer's disease and other neurodegenerative disorders. 1067 49

FE65 is a key "adapter" protein that links a multiprotein complex to an intracellular domain of beta-amyloid precursor protein (betaPP). Its overexpression modulates the trafficking of betaPP and facilitates the generation of beta-amyloid (Abeta). FE65 is predominantly expressed in brain tissues. An exon 9-inclusive isoform is exclusively expressed in neurons, and an exon 9-exclusive isoform is only expressed in non-neuronal cells. We quantitated the two isoforms in middle temporal cortex, middle frontal cortex, cerebellar cortex and caudate nucleus of 17 Alzheimer disease (AD) patients, 12 normal controls and 9 non-AD neurodegenerative disease controls by reverse transcription-competitive polymerase chain reaction (RT-cPCR). Expression of the two isoforms was significantly and differentially altered, with a 30-57% decrease in levels of the neuronal form (P < 0.05-0.002) and a 73-135% increase in levels of non-neuronal form (P < 0.02-0.001), in the temporal and frontal cortex of AD brains. These alterations presumably reflect advanced neurodegenerative processes of these regions. Surprisingly, expression of both isoforms was significantly up-regulated by 42-66% in the cerebellar cortex and caudate nucleus of AD brains when compared to normal brains (P < 0.05-0.005). Diffuse Abeta-positive plaques were observed in the cerebellum of these AD subjects but not in the normal controls. Selective up-regulation of only the FE65 neuronal isoform was seen in the cerebellar cortex in association with other neurodegenerative diseases (largely Parkinson's disease). Because FE65 modulates trafficking of betaPP toward the production of Abeta, the up-regulation of FE65 in AD cerebellum may be relevant to the genesis of diffuse plaques. Thus, early biochemical alterations in AD, not complicated by advanced pathology, may be beneficially investigated in the less-affected regions of the brain, such as the cerebellum.
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PMID:Broadly altered expression of the mRNA isoforms of FE65, a facilitator of beta amyloidogenesis, in Alzheimer cerebellum and other brain regions. 1072 70

Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.
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PMID:Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. 1088 78

Neuroprotective activity of estrogens is reported in Alzheimer disease and recently has also been suggested for Parkinson disease, a disease affecting more men than women. To characterize this estrogenic activity, we studied the effects of 17beta- and 17alpha-estradiol treatment (1 microg twice daily 5 days before, during the day of four MPTP (15 mg/kg) injections, and for the following 5 days) on dopamine striatal toxicity induced by the neurotoxin MPTP in retired breeder male C57BL/6 mice. Striatal dopamine concentrations and its metabolites dihydroxyphenylacetic acid and homovanillic acid measured by HPLC in MPTP mice that received 17beta-estradiol were comparable to control animals, whereas MPTP mice treated with saline or 17alpha-estradiol showed important decreases of dopamine and its metabolites. Striatal serotonin and its metabolite 5-hydroxyindoleacetic acid concentrations remained unchanged after MPTP and treatments with steroids. Striatal [(3)H]GBR 12935 binding autoradiography to the dopamine transporter was as extensively decreased and correlated with dopamine depletion in MPTP mice, whereas this transporter mRNA decrease in the substantia nigra pars compacta was less pronounced. Treatment with steroids did not significantly change [(3)H]GBR 12935 binding, whereas dopamine transporter mRNA levels were not significantly different from controls. Under the present paradigm in retired breeder male mice, our results show dopaminergic and stereospecificity of estradiol to augment dopamine levels in MPTP-lesioned mice without protecting against the extensive loss of dopamine terminals and moderate cell body loss.
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PMID:Stereospecific prevention by 17beta-estradiol of MPTP-induced dopamine depletion in mice. 1089 61

Recently, mutations of the alpha-synuclein gene were found to cause dominantly inherited Lewy-body Parkinson's disease (PD) and alpha-synuclein was identified as a major component of the Lewy body. However, the cause of the common form of PD, with a multifactorial rather than autosomal dominant inheritance pattern, remains unknown. Alpha-synuclein precipitates slowly and apparently spontaneously at high concentration in solution and the mutations that cause PD accelerate precipitation. Other dominantly inherited late-onset or adult-onset dominantly inherited neurodegenerative diseases are associated with precipitation of proteins. In Alzheimer disease, beta-amyloid and tau abnormalities are present and in prion disorders, prion proteins are found. In Huntington disease, a disorder with expanded CAG repeats, huntingtin precipitates occur. In dominantly inherited spinocerebellar ataxias, also expanded CAG repeat disorders, the corresponding ataxin protein precipitates are found. In multiple system atrophy, alpha-synuclein precipitates are encountered and in progressive supranuclear palsy, tau precipitates occur. In familial amyotrophic lateral sclerosis, a group of dominantly inherited disorders, SOD1 precipitates are found. Most of these disorders can involve the basal ganglia in some way. Since similar processes seem to affect neurons of adults or older individuals and since a relatively limited group of proteins seems to be involved, each producing a form of neurodegeneration, it is possible that certain common features are present that affect this group of proteins. Candidates include a conformational shift, as in prions, an abnormality of the ubiquitin-proteosome pathway, as seen in PD, an abnormality of a pathway preventing precipitation (e.g. chaperonins), or potentiation of a pathway promoting precipitation (e.g. gamma-glutamyl-transpeptidase) or apoptosis. Elucidation of the pathways causing this protein insolubilisation is the first step towards approaching prevention and reversal in these late-onset neurodegenerative diseases.
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PMID:Late-onset neurodegenerative diseases--the role of protein insolubility. 1092 91


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