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)

Reactive oxygen species, such as superoxide radicals, are thought to underlie the pathogenesis of various diseases. Almost 3 to 10% of the oxygen utilized by tissues is converted to its reactive intermediates, which impair the functioning of cells and tissues. Superoxide dismutase (SOD) catalyzes the conversion of single electron reduced species of molecular oxygen to hydrogen peroxide and oxygen. There are several classes of SOD that differ in their metal binding ability, distribution in different cell compartments, and sensitivity to various reagents. Among these, Cu, Zn superoxide dismutase (SOD1) is widely distributed and comprises 90% of the total SOD. This ubiquitous enzyme, which requires Cu and Zn for its activity, has great physiological significance and therapeutic potential. The present review describes the role of SODs, especially Cu, Zn SOD, in several diseases, such as familial amyotrophic lateral sclerosis (FALS), Parkinson's disease, Alzheimer's disease, dengue fever, cancer, Down's syndrome, cataract, and several neurological disorders. Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis. The mechanism by which mutant SOD1 causes the degeneration of motor neurons is not well understood. Transgenic mice expressing multiple copies of FALS-mutant SOD1s develop an ALS-like motor neuron disease. Vacuolar degeneration of mitochondria has been identified as the main pathological feature associated with motor neuron death and paralysis in several lines of FALS-SOD1 mice. Various observations and conclusions linking mutant SOD1 and FALS are discussed in this review in detail.
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PMID:Superoxide dismutase--applications and relevance to human diseases. 1221 58

The development of oxidative stress, in which production of highly reactive oxygen species (ROS) overwhelms antioxidant defenses, is a feature of many neurological diseases: ischemic, inflammatory, metabolic and degenerative. Oxidative stress is increasingly implicated in a number of neurodegenerative disorders characterized by abnormal filament accumulation or deposition of abnormal forms of specific proteins in affected neurons, like Alzheimer's disease (AD), Pick's disease, Lewy bodies related diseases, amyotrophic lateral sclerosis (ALS), and Huntington disease. Causes of neuronal death in neurodegenerative diseases are multifactorial. In some familiar cases of ALS mutation in the gene for Cu/Zn superoxide dismutase (SOD1) can be identified. In other neurodegenerative diseases ROS have some, usually not clear, role in early pathogenesis or implications on neuronal death in advanced stages of illness. The effects of oxidative stress on "post-mitotic cells", such as neurons may be cumulative, hence, it is often unclear whether oxidative damage is a cause or consequence of neurodegeneration. Peroxidation of cellular membrane lipids, or circulating lipoprotein molecules generates highly reactive aldehydes among which one of most important is 4-hydroxynonenal (HNE). The presence of HNE is increased in brain tissue and cerebrospinal fluid of AD patients, and in spinal cord of ALS patients. Immunohistochemical studies show presence of HNE in neurofibrilary tangles and in senile plaques in AD, in the cytoplasm of the residual motor neurons in sporadic ALS, in Lewy bodies in neocortical and brain stem neurons in Parkinson's disease (PD) and in diffuse Lewy bodies disease (DLBD). Thus, increased levels of HNE in neurodegenerative disorders and immunohistochemical distribution of HNE in brain tissue indicate pathophysiological role of oxidative stress in these diseases, and especially HNE in formation of abnormal filament deposites.
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PMID:4-hydroxynonenal and neurodegenerative diseases. 1289 7

In 1995, it was suggested that immature stem cells (Berashis Cells) existing in human cord blood might have an ameliorating effect on such neurological diseases as Alzheimer's, amyotrophic lateral sclerosis and Parkinson's disease. Since these predictions, we have been able to successfully extend the length of life of mice with amyotrophic lateral sclerosis [B6SJL-TgN(SOD1-G93A)IGUR], Huntington's Disease (B6CBA-TgN(H.Dexon1)62Gpb and Alzheimer's mice [Tg(HuAPP695.SWE)2576]. Recently we expanded the studies to include mice with Parkinson's Disease. 32 mice, 6-12 weeks old B6CBACa-AW-J/A-Kcnj6<wv> were obtained from Jackson Laboratory, Bar Harbor, Maine. The mice were divided into 3 groups: (A) 10 untreated control mice, (B) 10 mice treated with 5.6 x 10(6) congenic bone marrow mononuclear cells and (C) 12 mice receiving 100-110 x 10(6) HUCB mononuclear cells intravenously. No immunosuppression was used. When 50% of the controls were dead only 1 of the 10 mice receiving congenic marrow and 2 out of 12 mice that received cord blood mononuclear cells were dead. This preliminary study was terminated when the animal's were 200 days old, at that time one out of 10 controls was alive. Out of 10 mice that received congenic bone marrow, 2 were alive. Out of 12 mice that received megadoses of cord blood mononuclear cells 4 were alive. Survival curve of mice that had congenic marrow had a p value of <.05; the survival curve of mice receiving cord blood mononuclear cells had a p value <.001 (Fig 1) compared to controls. Human umbilical cord blood mononuclear cells significantly delayed the onset of symptoms and death of Parkinson's disease mice. This effect was greater than that produced by congenic bone marrow cells.
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PMID:Parkinson's disease mice and human umbilical cord blood. 1293 16

Both blood vessels and nerves are guided to their target. Vascular endothelial growth factor (VEGF)A is a key signal in the induction of vessel growth (a process termed angiogenesis). Though initial studies, now a decade ago, indicated that VEGF is an endothelial cell-specific factor, more recent findings revealed that VEGF also has direct effects on neural cells. Genetic studies showed that mice with reduced VEGF levels develop adult-onset motor neuron degeneration, reminiscent of the human neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Additional genetic studies confirmed that VEGF is a modifier of motor neuron degeneration in humans and in SOD1(G93A) mice--a model of ALS. Reduced VEGF levels may promote motor neuron degeneration by limiting neural tissue perfusion and VEGF-dependent neuroprotection. VEGF also affects neuron death after acute spinal cord or cerebral ischemia, and has also been implicated in other neurological disorders such as diabetic and ischemic neuropathy, nerve regeneration, Parkinson's disease, Alzheimer's disease and multiple sclerosis. These findings have raised growing interest in assessing the therapeutic potential of VEGF for neurodegenerative disorders.
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PMID:VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. 1535 65

Although oxidative stress has been strongly implicated in the pathogenesis of Alzheimer disease (AD) and Parkinson disease (PD), the identities of specific protein targets of oxidative damage remain largely unknown. Here, we report that Cu,Zn-superoxide dismutase (SOD1), a key antioxidant enzyme whose mutations have been linked to autosomal dominant neurodegenerative disorder familial amyotrophic lateral sclerosis (ALS), is a major target of oxidative damage in AD and PD brains. By using a combination of two-dimensional gel electrophoresis, immunoblot analysis, and mass spectrometry, we have identified four human brain SOD1 isoforms with pI values of 6.3, 6.0, 5.7, and 5.0, respectively. Of these, the SOD1 pI 6.0 isoform is oxidatively modified by carbonylation, and the pI 5.0 isoform is selectively accumulated in AD and PD. Moreover, Cys-146, a cysteine residue of SOD1 that is mutated in familial ALS, is oxidized to cysteic acid in AD and PD brains. Quantitative Western blot analyses demonstrate that the total level of SOD1 isoforms is significantly increased in both AD and PD. Furthermore, immunohistochemical and double fluorescence labeling studies reveal that SOD1 forms proteinaceous aggregates that are associated with amyloid senile plaques and neurofibrillary tangles in AD brains. These findings implicate, for the first time, the involvement of oxidative damage to SOD1 in the pathogenesis of sporadic AD and PD. This work suggests that AD, PD, and ALS may share a common or overlapping pathogenic mechanism(s) that could potentially be targeted by similar therapeutic strategies.
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PMID:Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. 1565 87

Selegiline, a therapeutic agent of Parkinson's disease, is known to have neuroprotective properties that may involve its regulatory effects on antioxidant enzymes. We evaluated effects of selegiline on activities of catalase (CAT), Cu,Zn-superoxide dismutase (SOD1) and Mn-SOD (SOD2) in the striatum, cortex and hippocampus of 8- and 25-week-old rats, and on SOD activities and glutathione levels in mesencephalic slice cultures. Selegiline (2 mg/kg) significantly increased CAT and SOD2 activities in the striatum, but not in the cortex and hippocampus, of 25-week-old rats. In contrast, selegiline failed to increase CAT and SOD activities in three brain regions of 8-week-old rats, whereas L: -dopa significantly increased SOD1 activity in the striatum. In slice cultures, selegiline increased SOD1 and SOD2 activities with a maximal effective concentration of 10(-8) and 10(-10) M, respectively. Moreover, selegiline significantly increased glutathione level. These results suggest that selegiline can decrease oxidative stress in nigrostriatum by augmenting various antioxidant systems, each of which responds optimally to different concentrations of selegiline.
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PMID:Effects of selegiline on antioxidant systems in the nigrostriatum in rat. 1595 53

Cell replacement therapy has been widely suggested as a treatment for multiple diseases including motor neuron disease. A variety of donor cells have been tested for treatment including isolated preparations from bone marrow and embryonic spinal cord. Another cell source, Sertoli cells, have been successfully used in models of diabetes, Parkinson's disease and Huntington's disease. The ability of these cells to secrete cytoprotective proteins and their role as 'nurse cells' supporting the function of other cell types in the testes suggest their potential use as neuroprotective cells. The current study examines the ability of Sertoli cells injected into the parenchyma of the spinal cord to protect motor neurons in a mouse model for amyotrophic lateral sclerosis. Seventy transgenic mice expressing the mutant (G93A) human Cu-Zn superoxide dismutase (SOD1) received a unilateral spinal injection of Sertoli-enriched testicular cells into the L4-L5 ventral horn (1 x 10(5) cells total) prior to the onset of clinical symptoms. The animals were euthanized at the end stage of the disease. Histological and morphometric analyses of the transplant site were performed. A significant increase in the number of surviving ChAT positive motor neurons was found ipsilateral to the injection compared with contralateral and uninjected spinal cord. The ipsilateral increase in motor neuron density was dependent upon proximity to the injection site. Sections rostral or caudal to the injection site did not display a similar difference in motor neuron density. Implantation of a Sertoli-cell-enriched preparation has a significant neuroprotective benefit to vulnerable motor neurons in the SOD1 transgenic model. The therapeutic benefit may be the result of secreted neurotrophic factors present at a critical stage of motor neuron degeneration in this model.
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PMID:Sertoli cells improve survival of motor neurons in SOD1 transgenic mice, a model of amyotrophic lateral sclerosis. 1624 26

In this follow-up study concentration, oxidative activity and specific oxidative activity of ceruloplasmin (CP) in serum and the activity of superoxide dismutase (SOD1) in erythrocytes were reexamined in 28 of originally 40 patients with Parkinson's disease (PD), and their age- and gender-matched controls. The mean CP and SOD1 parameters were significantly lower in the patients than in the controls. SOD1 activity and age of the patients were inversely correlated. The patients were divided into two subgroups based on their H&Y score i.e. groups II and III (12 patients) versus groups IV and V (16 patients). No significant difference was found in the CP or SOD1 parameters between the subgroups. Patients were also divided into two subgroups based on treatment with levodopa and decarboxylase blocker alone (12 patients) or given additionally a dopamine agonist (15 patients). No significant difference in the parameters was found between these subgroups in relation to intake of dopamine agonists. Results of this study are in agreement with results of the former study 5 years earlier. There is considerable overlap in individual values between patients and controls of the parameters studied. Thus CP and SOD1 have no obvious value for diagnosis or clinical evaluation of PD.
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PMID:Ceruloplasmin and superoxide dismutase (SOD1) in Parkinson's disease: a follow-up study. 1635 11

Oxidative stress has been suggested to be an important mediator of dopaminergic cell death in Parkinson's disease (PD). We investigated the neuroprotective potential of Cu/Zn superoxide dismutase (SOD1) overexpression in the rat substantia nigra (SN) following adenovirus-mediated gene transfer. Human dopaminergic SK-N-SH cells were transduced with adenoviral vectors expressing either human SOD1 (Ad-SOD1) or beta-galactosidase (Ad-betagal) before exposure to 1 mM of the 1-methyl-4-phenylpyridinium ion (MPP+). A strong neuroprotective effect of SOD1 gene transfer was observed in the SK-N-SH cells exposed to MPP+ compared with controls. Adult rats were then given unilateral injections of either Ad-SOD1 or Ad-betagal into the striatum, and MPP+ was administered 8 days later at the same location. Strong transgene expression was detected in the SN dopaminergic neurons, a consequence of retrograde axonal transport of the adenoviral particles. The amphetamine-induced rotational behavior of the rats was markedly lower in Ad-SOD1-injected rats than in control animals. Also, behavioral recovery significantly correlated with the number of tyrosine hydrolase-expressing neurons in the SN of the treated rats. These results are consistent with oxidative stress contributing to the MPP+ -induced neurodegenerative process. They also indicate that SOD1 gene transfer into the nigrostriatal system may be a potential neuroprotective strategy for treating PD.
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PMID:1-methyl-4-phenylpyridinium neurotoxicity is attenuated by adenoviral gene transfer of human Cu/Zn superoxide dismutase. 1635 38

In many of autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with Cu/Zn superoxide dismutase (SOD1) mutation, a missense point mutation may induce the disease by its gain of adverse property. Similar 'gain of toxic function' of mutant protein is predicted to cause cell death in other autosomal dominant neurodegenerative diseases such as familial Alzheimer disease, prion disease, polyglutamine diseases and Parkinson disease. In all these familial diseases, one rational approach to therapy is to develop a method to specifically eliminate the aberrant protein. Duplex of 21-nt RNA, known as siRNA, has recently emerged as a powerful tool to silence gene. Mutant-allele specific gene silencing with siRNA was showed in familial ALS and Machado-Joseph diseases. We made the transgenic (Tg) mouse of modified small interfering RNA (siRNA). By crossing this anti-SOD1 siRNA Tg mouse with a SOD1(G93A) Tg mouse as a model for ALS, siRNA halted the development of disease by inhibiting mutant G93A SOD1. Our results support the feasibility of utilizing siRNA-based gene therapy of neurodegenerative diseases of autosomal dominant inheritance.
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PMID:[RNAi and neurological disease]. 1644 77


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