Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most frequent genetic causes of amyotrophic lateral sclerosis (ALS) determined so far are mutations occurring in the gene for copper/zinc superoxide dismutase (CuZnSOD). The mechanism may involve inappropriate formation of hyroxyl radicals, peroxynitrite or malfunctioning of the SOD protein. We hypothesized that undiscovered genetic causes of sporadically occurring amyotrophic lateral sclerosis might be found in the mechanisms that create and destroy oxygen free radicals within the cell. After determining that there were no CuZnSOD mutations present, we measured superoxide production from mitochondria and manganese superoxide dismutase (MnSOD), glutathione peroxidase, NFkappaB, Bcl-2 and Bax by immunoblot. Of the ten sporadic patients we tested we found three patients with significantly increased concentrations of MnSOD. These patients also had lower levels of superoxide production from mitochondria and decreased expression of Bcl-2. No mutations were found in the cDNA sequence of either MnSOD in any of the sporadic patients. A patient with a CuZnSOD mutation (G82R) used as a positive control showed none of these abnormalities. The patients displaying the MnSOD aberrations showed no specific distinguishing features. This result suggests that the cause of ALS in a subgroup of ALS patients (30%) is genetic in origin and can be identified by these markers. The alteration in MnSOD and Bcl-2 are likely epiphenomena resulting from the primary genetic defect. It suggests also that the oxygen free radicals are part of the cause in this subgroup and that dysregulation of MnSOD or increased endogenous superoxide production might be responsible.
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PMID:Manganese superoxide dismutase levels are elevated in a proportion of amyotrophic lateral sclerosis patient cell lines. 1087 11

The present study set out to define the possible effect of reduced glutathione (GSH), the substrate of glutathione peroxidase (GSH-Px), a free radical inactivating enzyme, in amyotrophic lateral sclerosis (ALS). Thirty-two patients affected by definite ALS seen in our institution between August 1993 and July 1994 were admitted to the study. The effect of GSH was studied in an open, crossover, randomized study. GSH was given at the dose of 600 mg each day intramuscularly for 12 weeks. The patients, taken sequentially, were randomly assigned to two groups. The first group received the drug while the second received only symptomatic therapies for 12 weeks. After a week of washout, the second group received GSH and the first only symptomatic therapies for 12 weeks. The rate of progression of the diseases was compared in the two groups. Clinical evaluation included manual test for muscle strength, Norris scale, bulbar scale, and forced vital capacity (FVC) percent. No significant difference was found in the progression of ALS in the two periods, although a slight slowing of the disease progression rate was found during the period of treatment, probably related to the open design of the study. Our data do not show any significant effect of reduced glutathione in modifying the progression of ALS.
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PMID:Reduced glutathione in amyotrophic lateral sclerosis: an open, crossover, randomized trial. 1093 31

Patients with Down's syndrome (DS) show elevated levels of copper, zinc-containing superoxide dismutase (SOD1) and appear to have increased lipid peroxidation and oxidative damage to DNA as well as elevated glutathione peroxidase activity. Increasing SOD1 levels by gene transfection in NT-2 and SK-N-MC cell lines also led to a rise in glutathione peroxidase activity, but this was nevertheless accompanied by decreased proliferation rates, increased lipid peroxidation and protein carbonyls, and a trend to a rise in 8-hydroxyguanine and protein-bound 3-nitrotyrosine. Transfection of these cell lines with DNA encoding two mutant SOD1 enzymes (G37R and G85R) associated with familial amyotrophic lateral sclerosis (FALS), produced similar, but more severe changes, i.e. even lower growth rates, higher lipid peroxidation, 3-nitrotyrosine and protein carbonyl levels, decreased GSH levels, raised GSSG levels and higher glutathione peroxidase activities. Since G85R has little SOD activity, these changes cannot be related to increased O(2)(-) scavenging. In no case was SOD2 (mitochondrial Mn-SOD) level altered. Our cellular systems reproduce many of the biochemical changes observed in patients with DS or ALS, and in transgenic mice overexpressing mutant SOD1. They also show the potentially deleterious effects of SOD1 overexpression on cellular proliferation, which may be relevant to abnormal development in DS.
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PMID:Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative damage and antioxidant defences: relevance to Down's syndrome and familial amyotrophic lateral sclerosis. 1118 15

In recent years, oxidative stress has been implicated in a variety of degenerative processes, diseases, and syndromes. Some of these include atherosclerosis, myocardial infarction, stroke, and ischemia/reperfusion injury; chronic and acute inflammatory conditions such as wound healing; central nervous system disorders such as forms of familial amyotrophic lateral sclerosis (ALS) and glutathione peroxidase-linked adolescent seizures; Parkinson's disease and Alzheimer's dementia; and a variety of other age-related disorders. Among the various biochemical events associated with these conditions, emerging evidence suggests the formation of superoxide anion and expression/activity of its endogenous scavenger, superoxide dismutase (SOD), as a common denominator. This review summarizes the function of SOD under normal physiological conditions as well as its role in the cellular and molecular mechanisms underlying oxidative tissue damage and neurological abnormalities. Experimental evidence from laboratory animals that either overexpress (transgenics) or are deficient (knockouts) in antioxidant enzyme/protein levels and the genetic SOD mutations observed in some familial cases of ALS are also discussed.
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PMID:Role of superoxide dismutases in oxidative damage and neurodegenerative disorders. 1219 1

Evidence of oxidative stress is apparent in both acute and chronic neurodegenerative diseases, such as stroke, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Increased generation of reactive oxygen species simply overwhelm endogenous antioxidant defences, leading to subsequent oxidative damage and cell death. Tissue culture and animal models have been developed to mimic some of the biochemical changes and neuropathology found in these diseases. In doing so, it has been experimentally demonstrated that oxidative stress plays a critical role in neuronal cell death. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) have demonstrated therapeutic efficacy in models of neurodegeneration. However, delivery and stability issues have reduced the enthusiasm to clinically develop these proteins. Most recently, SOD mimetics, small molecules which mimic the activity of endogenous superoxide dismutase, have come to the forefront of antioxidant therapeutics. This review will examine the experimental evidence supporting the use of scavengers of superoxide anions in treating some neurodegenerative diseases, such as stroke, PD and ALS, but also the pitfalls that have met antioxidant molecules in clinical trials.
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PMID:Oxidative stress in neurodegenerative diseases: therapeutic implications for superoxide dismutase mimetics. 1271 37

Glutamate excitotoxicity is implicated in the aetiology of amyotrophic lateral sclerosis (ALS) with impairment of glutamate transport into astrocytes a possible cause of glutamate-induced injury to motor neurons. It is possible that mutations of Cu/Zn superoxide dismutase (SOD1), responsible for about 20% of familial ALS, down-regulates glutamate transporters via oxidative stress. We transfected primary mouse astrocytes to investigate the effect of the FALS-linked mutant hSOD1(G93A) and wild-type SOD1 (hSOD1wt) on the glutamate uptake system. Using western blotting, immunocytochemistry and RT-PCR it was shown that expression of either hSOD1(G93A) or hSOD1wt in astrocytes produced down-regulation of the levels of a glutamate transporter GLT-1, without alterations in its mRNA level. hSOD1(G93A) or hSOD1wt expression caused a decrease of the monomeric form of GLT-1 without increasing oxidative multimers of GLT-1. The effects were selective to GLT-1, since another glutamate transporter GLAST protein and mRNA levels were not altered. Reflecting the decrease in GLT-1 protein, [3H]d-aspartate uptake was reduced in cultures expressing hSOD1(G93A) or hSOD1wt. The hSOD1-induced decline in GLT-1 protein and [3H]d-aspartate uptake was not blocked by the antioxidant Trolox nor potentiated by antioxidant depletion using catalase and glutathione peroxidase inhibitors. Measurement of 2',7'-dichlorofluorescein (DCF)-induced fluorescence revealed that expression of hSOD1(G93A) or hSOD1wt in astrocytes does not lead to detectable increase of intracellular reactive oxygen species. This study suggests that levels of GLT-1 protein in astrocytes are reduced rapidly by overexpression of hSOD1, and is due to a property shared between the wild-type and G93A mutant form, but does not involve the production of intracellular oxidative stress.
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PMID:Expression of SOD1 G93A or wild-type SOD1 in primary cultures of astrocytes down-regulates the glutamate transporter GLT-1: lack of involvement of oxidative stress. 1469 May 36

The brain is deficient in oxidative defense mechanisms and hence is at greater risk of damage mediated by reactive oxygen species (ROS) resulting in molecular and cellular dysfunction. Emerging evidence suggesting the activation of glutamate gated cation channels, may be another source of oxidative stress, leading to neuronal degeneration. Oxidative stress has been implicated in the development of neurodegenerative diseases like Parkinsonism, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epileptic seizures, and stroke. Melatonin, the pineal hormone, acts as a direct free radical scavenger and indirect antioxidant. It is suggested that the increase in neurodegenerative diseases is attributable to a decrease in the levels of melatonin with age. Melatonin has been shown to either stimulate gene expression for the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) or to increase their activity. Additionally, it neutralizes hydoxyl radical, superoxide radical, peroxyl radical, peroxynitrite anion, singlet oxygen, hydrogen peroxide, nitric oxide, and hypochlorous acid. Unlike other antioxidants, melatonin can easily cross all morphophysiological barriers, e.g., the blood brain barrier, and enters cells and subcellular compartments. Though evidence are accumulating to suggest the potential of melatonin in neurodegenerative conditions, much information needs to be generated before the drug can find place in neurology clinics.
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PMID:Neuroprotective role of melatonin in oxidative stress vulnerable brain. 1526 48

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

Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPxl were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPxl-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death.
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PMID:Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models. 1598 30

Histological rescue of superoxide dismutase1 (SOD1)-mutated hepatocytes from mutant SOD1 stress is investigated from the viewpoint of upregulation of the redox system [peroxiredoxin (Prx) and glutathione peroxidase (GPx)]. Histopathological and immunohistochemical studies using antibodies against PrxI/PrxII/GPxI were carried out on specimens from four different strains of animal models of mutant SOD1-linked familial amyotrophic lateral sclerosis (ALS). In the livers of the ALS animal models in the presymptomatic stage without motor neuron loss, both swollen and eosinophilic hepatocytes with vacuolation pathology were observed. After developing motor deficits, this swelling and vacuolation ceased to be apparent. In the terminal stage when severe motor neuron loss was observed, these hepatocytes recovered and appeared normal. In redox system-related immunohistochemical preparations, almost all of the normal hepatocytes expressed the redox system-related enzymes PrxI/PrxII/GPxI. In the presymptomatic stage, some hepatocytes did not express redox system-related enzymes. After clinical onset, over 75% of hepatocytes showed overexpression of PrxI/PrxII/GPxI, i. e., upregulation of the redox system. At the end stage, near normal PrxI/PrxII/GPxI expression was observed again in the hepatocytes. Redox system upregulation in SOD1-mutated hepatocytes rescues hepatocytes from the mutant SOD1 stress that leads to motor neuron death.
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PMID:Histological recovery of the hepatocytes is based on the redox system upregulation in the animal models of mutant superoxide dismutase (SOD)1-linked amyotrophic lateral sclerosis. 1659 72


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