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)

Copper-zinc superoxide dismutase (SOD1)-like immunoreactivity has been demonstrated in Lewy body-like inclusions (LIs) in brain tissues from patients with familial and sporadic amyotrophic lateral sclerosis. Using immunocytochemistry, we studied Lewy bodies (LBs), the original inclusions from which the term LI was derived, in five patients with Parkinson disease (PD). Surprisingly, many LBs were immunostained by an antibody against SOD1. There were two types of staining pattern: a diffuse pattern, and a peripheral pattern with an unstained core. An immunoelectron microscopic study demonstrated that the immunoreactive products were restricted to the fibrillary profiles, sparing the unstructured core. Our results showed that SOD1-like immunoreactivity occurred frequently in LBs and LIs, suggesting that a common cytopathological process is responsible for the formation of LB-type neuronal intracytoplasmic inclusions. Our results also suggest that SOD1 plays a role in the neurodegeneration associated with PD.
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PMID:Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson disease: a light and electron microscopic immunocytochemical study. 767 2

Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an [18F]6-fluoro-L-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain-derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precursor protein (APP, 21q21), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.
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PMID:Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes. 791 97

Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.
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PMID:Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. 926 33

This article reviews current knowledge of neurofilament structure, phosphorylation, and function and neurofilament involvement in disease. Neurofilaments are obligate heteropolymers requiring the NF-L subunit together with either the NF-M or the NF-H subunit for polymer formation. Neurofilaments are very dynamic structures; they contain phosphorylation sites for a large number of protein kinases, including protein kinase A (PKA), protein kinase C (PKC), cyclin-dependent kinase 5 (Cdk5), extracellular signal regulated kinase (ERK), glycogen synthase kinase-3 (GSK-3), and stress-activated protein kinase gamma (SAPK gamma). Most of the neurofilament phosphorylation sites, located in tail regions of NF-M and NF-H, consist of the repeat sequence motif, Lys-Ser-Pro (KSP). In addition to the well-established role of neurofilaments in the control of axon caliber, there is growing evidence based on transgenic mouse studies that neurofilaments can affect the dynamics and perhaps the function of other cytoskeletal elements, such as microtubules and actin filaments. Perturbations in phosphorylation or in metabolism of neurofilaments are frequently observed in neurodegenerative diseases. A down-regulation of mRNA encoding neurofilament proteins and the presence of neurofilament deposits are common features of human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. Although the extent to which neurofilament abnormalities contribute to pathogenesis in these human diseases remains unknown, emerging evidence, based primarily on transgenic mouse studies and on the discovery of deletion mutations in the NF-H gene of some ALS eases, suggests that disorganized neurofilaments can provoke selective degeneration and death of neurons. An interference of axonal transport by disorganized neurofilaments has been proposed as one possible mechanism of neurofilament-induced pathology. Other factors that can potentially lead to the accumulation of neurofilaments will be discussed as well as the emerging evidence for neurofilaments as being possible targets of oxidative damage by mutations in the superoxide dismutase enzyme (SOD1); such mutations are responsible for approximately 20% of familial ALS cases.
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PMID:Neurofilaments in health and disease. 975 17

Hydroxyl radical (.OH) levels in blood, superoxide dismutase (SOD) activity in plasma (plasma-SOD) and in red blood cells (RBC) relative to Cu,Zn-SOD (SOD1) protein (RBC-SOD/SOD1), SOD1 protein in RBC (SOD1/RBC) and plasma (SOD1/plasma), and Mn-SOD protein in plasma (SOD2/plasma) were measured in patients with Parkinson's disease (PD), multiple-system atrophy (MSA) with parkinsonism, and in control subjects. Patients with PD had significantly higher.OH and plasma-SOD values and significantly lower RBC-SOD/SOD1 and SOD1/RBC values than the corresponding MSA and control values. In PD, RBC-SOD/SOD1 values were significantly lower in older patients and were negatively correlated with age.OH levels were significantly higher in PD patients with early onset, a long period of illness or severe Yahr stage, and were negatively correlated with onset and positively correlated with duration of illness. RBC-SOD/SOD1 values in PD patients who received pergolide therapy were significantly higher than those in PD patients who received neither pergolide nor bromocriptine therapy. Therefore, the higher.OH level and the lower SOD1 activity may play a role in the onset and progression of PD, and pergolide may act neuroprotectively by inducing SOD1 activity.
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PMID:Hydroxyl radical and superoxide dismutase in blood of patients with Parkinson's disease: relationship to clinical data. 1056 21

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

A major risk factor for neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) is aging. Two processes that have been implicated in aging are free radical-induced oxidative damage and mitochondrial dysfunction. A progressive impairment of mitochondrial function and/or increased oxidative damage has been suggested to play critical roles in the pathogenesis of these neurodegenerative diseases. For example, decreased complex I activity, increased oxidative damage and altered activities of antioxidant defense enzymes have been demonstrated in PD. In AD, decrements in complex IV activity and increased oxidative damage have been reported. Reductions in complex II activity, increased cortical lactate levels and oxidative damage have been described in HD. Some familial ALS cases are associated with mutations in the gene for Cu,Zn superoxide dismutase (SOD1) while increased oxidative damage is observed in sporadic ALS. Studies in PSP have demonstrated regionally specific reductions in brain and muscle mitochondrial function, hypofrontality and increased oxidative damage. Altogether, the age-dependent onset and progressive course of these neurodegenerative diseases may ultimately highlight an association between aging, mitochondrial impairment and oxidative stress.
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PMID:Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. 1096 26

Oxidative stress reactions may contribute to the pathogenesis of Parkinson's disease (PD). The superoxide dismutases potentially play significant roles in PD by detoxifying superoxide radical. We developed genomic DNA and cDNA-based sequencing assays to identify genetic variants in the copper/zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes. No genetic variants were detected in the gene encoding SOD1 in DNA from 45 idiopathic PD cases and 49 controls from a population-based case-control study. However, we identified a previously described polymorphism of the mitochondrial targeting sequence consisting of a C47T in exon 2 of SOD2, which results in an alanine to valine substitution. We analyzed this SOD2 variant in DNA from 155 cases and 231 controls from the same study, using an allele-specific fluorogenic 5' nuclease assay, and found no differences in the distributions of allelic frequencies. These results indicate that SOD gene variants do not contribute to PD pathogenesis.
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PMID:Genetic polymorphisms of superoxide dismutase in Parkinson's disease. 1148 95

Two types of ubiquitinated inclusions have been described in motor neurone disease (MND). (1) Skein or globular ubiquitinated inclusions in the motor neurones (more frequently in the lower motor neurones). This is a characteristic feature of all motor neurone disease categories. (2) Dot-shape or crescentric ubiquitinated inclusions in the upper layers of cortex and dentate gyrus described in cases of motor neurone disease with dementia (DMND). We investigated the substantia nigra (SN) in MND cases; two cases of motor neurone disease inclusion body (MND-IB) dementia, six cases of DMND, 14 cases of MND (including one case from Guam and two cases of familial SOD1 mutation), four cases of Parkinson's disease (PD), and 10 cases of age-matched normal controls. SN and spinal cord sections were stained with ubiquitin (alpha-synuclein, tau, PGM1, SMI-31 and SOD1 antibodies). The neuronal density in SN was quantified by using a computer-based image analysis system. Four out of six DMND cases showed rounded ubiquitin positive inclusions with irregular frayed edges, associated with neuronal loss, reactive astrocytosis and a large number of activated microglia cells. These inclusions are negative with antibodies to (alpha-synuclein, tau, SMI-31 and SOD1). The SN in cases from MND-IB dementia and MND showed occasional neuronal loss and no inclusions. The ubiquitin-only inclusions in SN of DMND cases are similar (but not identical) to the ubiquitinated inclusions described previously in the spinal cord of MND cases and are distinct from Lewy bodies (LBs). The degeneration of SN is most likely a primary neurodegenerative process of motor neurone disease type frequently involving the DMND cases. MND disease is a spectrum and multisystem disorder with DMND located at the extreme end of a spectrum affecting the CNS more widely than just the motor system.
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PMID:Ubiquitin-only intraneuronal inclusion in the substantia nigra is a characteristic feature of motor neurone disease with dementia. 1197 98

Several mechanisms are thought to be involved in the progressive decline in neurons of the substantia nigra pars compacta (SNpc) that leads to Parkinson's disease (PD). Neurotoxin 6-hydroxydopamine (6-OHDA), which induces parkinsonian symptoms in experimental animals, is thought to be formed endogenously in patients with PD through dopamine (DA) oxidation and may cause dopaminergic cell death via a free radical mechanism. We therefore investigated protection against 6-OHDA by inhibiting oxidative stress using a gene transfer strategy. We overexpressed the antioxidative Cu/Zn-superoxide dismutase (SOD1) enzyme in primary culture dopaminergic cells by infection with an adenovirus carrying the human SOD1 gene (Ad-hSOD1). Survival of the dopaminergic cells exposed to 6-OHDA was 50% higher among the SOD1-producing cells than the cells infected with control adenoviruses. In contrast, no significant increased survival of (6-OHDA)-treated dopaminergic cells was observed when they were infected with an adenovirus expressing the H(2) O(2) -scavenging glutathione peroxidase (GPx) enzyme. These results underline the major contribution of superoxide in the dopaminergic cell death process induced by 6-OHDA in primary cultures. Overall, this study demonstrates that the survival of the dopaminergic neurons can be highly increased by the adenoviral gene transfer of SOD1. An antioxidant gene transfer strategy using viral vectors expressing SOD1 is therefore potentially beneficial for protecting dopaminergic neurons in PD.
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PMID:Neuronal transfer of the human Cu/Zn superoxide dismutase gene increases the resistance of dopaminergic neurons to 6-hydroxydopamine. 1209 70


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