Failure of the ubiquitin-proteasome system in Parkinson's disease.
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Animals↗
Biomedical subjects
P Jenner
Publications and source records attributed to P Jenner.
The central aromatic amino acid DOPA decarboxylase inhibitor, NSD-1015, does not inhibit L-DOPA-induced circling in unilateral 6-OHDA-lesioned-rats.
The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA. However, the effects of NSD-1015 on L-DOPA-induced motor activity are unclear as both increases and decreases have been reported. We now investigate the effects of NSD-1015 on L-DOPA-induced contralateral circling behaviour in 6-OHDA-lesioned rats and on striatal levels of L-DOPA, 3-O-methyl-DOPA (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) using microdialysis techniques. NSD-1015 (50-200 mg/kg i.p.) inhibited AADC activity both in the liver and striatum of normal rats. Administration of NSD-1015 (50-200 mg/kg i.p.), delayed the onset of circling produced by administration of L-DOPA (25 mg/kg i.p.) and carbidopa (12.5 mg/kg i. p.), suggesting blockade of central AADC activity. However, the duration of the L-DOPA-induced circling was prolonged and overall no inhibition of circling behaviour occurred. L-DOPA (25 mg/kg i.p.) plus carbidopa (12.5 mg/kg i.p.) increased extracellular levels of L-DOPA, 3-OMD, dopamine, DOPAC and HVA in the 6-OHDA-lesioned striatum. Pretreatment of rats with the central AADC inhibitor, NSD-1015 (100 mg/kg i.p.), potentiated the increase in dialysate levels of L-DOPA and 3-OMD. However, it did not reduce striatal dopamine levels in the 6-OHDA-lesioned hemisphere, which were elevated following L-DOPA administration. The increases in DOPAC and HVA levels were abolished by NSD-1015 pretreatment. These results suggest that, while NSD-1015 blocks central AADC activity, it also acts as a monoamine oxidase inhibitor so maintaining striatal dopamine concentration by reducing dopamine metabolism. NSD-1015, therefore, may not be an appropriate tool for the study of brain AADC activity and for assessing the neuromodulatory role of L-DOPA.
3,4-Dihydroxyphenylacetic Acid↗
Involvement of intrinsic cholinergic and GABAergic innervation in the effect of NMDA on striatal dopamine efflux and metabolism as assessed by microdialysis studies in freely moving rats.
Microdialysis perfusion was used to study the participation of striatal cholinergic and gamma-aminobutyric acid-ergic (GABAergic) neurotransmission in basal and N-methyl-D-aspartate (NMDA) receptor-modulated dopamine release and metabolism in the striatum of the freely moving rat. Reverse dialysis of atropine (1-50 microM) induced a concentration-related increase in dopamine efflux and decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) efflux. (+)-Bicuculline (10-100 microM) similarly increased dopamine efflux, but was without consistent effect on metabolite efflux. Reverse dialysis of NMDA (1 mM) evoked an approximately twofold increase in dopamine efflux and decreased DOPAC and HVA efflux to 30-40% of basal levels. The effect of NMDA on dopamine efflux was completely abolished by coadministration of tetrodotoxin (TTX; 1 microM) or atropine (10 microM), and markedly potentiated (approximately fourfold) by coadministration of (+)-bicuculline (50 microM). The NMDA-induced decrease in dopamine metabolite efflux was inhibited by coadministration of TTX or (+)-bicuculline, but was unaffected by atropine. Our data suggest that dopamine release in the striatum is subject to both cholinergic and GABAergic tonic inhibitory mechanisms mediated through muscarinic and GABAA receptors, respectively. Furthermore, NMDA-stimulated dopamine release also involves obligatory cholinergic facilitation and an inhibitory GABAergic component mediated through these respective receptors.
3,4-Dihydroxyphenylacetic Acid↗
Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson's syndrome and of MPTP-treated marmosets.
Recent evidence obtained in rat models of Parkinson's disease showed that the density of cannabinoid CB1 receptors and their endogenous ligands increase in basal ganglia. However, no data exists from post-mortem brain of humans affected by Parkinson's disease or from primate models of the disorder. In the present study, we examined CB1 receptor binding and the magnitude of the stimulation by WIN55,212-2, a specific CB1 receptor agonist, of [35S]GTPgammaS binding to membrane fractions from the basal ganglia of patients affected by Parkinson's disease. In Parkinson's disease, WIN55,212-2-stimulated [35S]GTPgammaS binding in the caudate nucleus, putamen, lateral globus pallidus and substantia nigra was increased, thus indicating a more effective activation of GTP-binding protein-coupled signalling mechanisms via CB1 receptors. This was accompanied by an increase in CB1 receptor binding in the caudate nucleus and the putamen, although no changes were observed in the lateral globus pallidus and the substantia nigra. Because Parkinson's disease patients had been chronically treated with l-DOPA, brains were studied from normal common marmosets and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animals with and without chronic L-DOPA treatment. MPTP-lesioned marmosets had increased CB1 receptor binding in the caudate nucleus and the putamen compared to control marmosets, as well as increased stimulation of [35S]GTPgammaS binding by WIN55,212-2. However, following l-DOPA treatment these parameters returned towards control values. The results indicate that a nigro-striatal lesion is associated with an increase in CB1 receptors in the basal ganglia in humans and nonhuman primates and that this increase could be reversed by chronic l-DOPA therapy. The data suggest that CB1 receptor blockade might be useful as an adjuvant for the treatment of parkinsonian motor symptoms.
Aged↗
GDNF reverses priming for dyskinesia in MPTP-treated, L-DOPA-primed common marmosets.
Parkinson's disease (PD) is associated with a progressive loss of dopamine neurons in the substantia nigra and degeneration of dopaminergic terminals in the striatum. Although L-DOPA treatment provides the most effective symptomatic relief for PD it does not prevent the progression of the disease, and its long-term use is associated with the onset of dyskinesia. In rodent and primate studies, glial cell line-derived neurotrophic factor (GDNF) may prevent 6-OHDA- or MPTP-induced nigral degeneration and so may be beneficial in the treatment of PD. In this study, we investigate the effects of GDNF on the expression of dyskinesia in L-DOPA-primed MPTP-treated common marmosets, exhibiting dyskinesia. GDNF or saline was administered by two intraventricular injections, 4 weeks apart, to MPTP-treated, L-DOPA-treated common marmosets primed to exhibit dyskinesia. Prior to GDNF or saline administration, all animals displayed marked dyskinesia when treated with L-DOPA. GDNF administration produced a significant improvement in motor disability and, following the second injection of GDNF, a significant improvement in the locomotor activity was observed. Following the administration of L-DOPA there was a greater reversal of disability and a reduction in the intensity of L-DOPA-induced dyskinesia in GDNF-treated animals compared to saline-treated controls. However, there was no significant difference in L-DOPA's ability to increase locomotor activity between GDNF-treated and saline-treated animals. GDNF treatment caused a significant increase in the number of tyrosine hydroxylase-positive neurons in the substantia nigra, but no change in [(3)H]mazindol binding to dopamine terminals was found in the striatum of GDNF-treated animals compared to saline-treated controls. In GDNF-treated animals a small but significant reduction in enkephalin mRNA was observed in the caudate nucleus but not in the putamen or the nucleus accumbens. Substance P mRNA expression was equally reduced in the caudate nucleus and the putamen of the GDNF-treated animals but not in the nucleus accumbens. Intraventricular administration of GDNF improved MPTP-induced disability and reversed dopamine cell loss in the substantia nigra. GDNF also diminished L-DOPA-induced dyskinesia, which may relate to its ability to partly restore nigral dopaminergic transmission or to modify the activity of striatal output pathways.
Animals↗
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.
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.
Aldehydes↗
Effect of the overexpression of wild-type or mutant alpha-synuclein on cell susceptibility to insult.
Mutations in alpha-synuclein (A30P and A53T) are involved in some cases of familial Parkinson's disease (FPD), but it is not known how they result in nigral cell death. We examined the effect of alpha-synuclein overexpression on the response of cells to various insults. Wild-type alpha-synuclein and alpha-synuclein mutations associated with FPD were overexpressed in NT-2/D1 and SK-N-MC cells. Overexpression of wild-type alpha-synuclein delayed cell death induced by serum withdrawal or H(2)O(2), but did not delay cell death induced by 1-methyl-4-phenylpyridinium ion (MPP(+)). By contrast, wild-type alpha-synuclein transfectants were sensitive to viability loss induced by staurosporine, lactacystin or 4-hydroxy-2-trans-nonenal (HNE). Decreases in glutathione (GSH) levels were attenuated by wild-type alpha-synuclein after serum deprivation, but were aggravated following lactacystin or staurosporine treatment. Mutant alpha-synucleins increased levels of 8-hydroxyguanine, protein carbonyls, lipid peroxidation and 3-nitrotyrosine, and markedly accelerated cell death in response to all the insults examined. The decrease in GSH levels was enhanced in mutant alpha-synuclein transfectants. The loss of viability induced by toxic insults was by apoptosic mechanism. The presence of abnormal alpha-synucleins in substantia nigra in PD may increase neuronal vulnerability to a range of toxic agents.
1-Methyl-4-phenylpyridinium↗
Effect of proteasome inhibition on cellular oxidative damage, antioxidant defences and nitric oxide production.
The ubiquitin/proteasome pathway plays an essential role in protein turnover in vivo, and contributes to removal of oxidatively damaged proteins. We examined the effects of proteasome inhibition on viability, oxidative damage and antioxidant defences in NT-2 and SK-N-MC cell lines. The selective proteasome inhibitor, lactacystin (1 microM) caused little loss of viability, but led to significant increases in levels of oxidative protein damage (measured as protein carbonyls), ubiquitinated proteins, lipid peroxidation and 3-nitrotyrosine, a biomarker of the attack of reactive nitrogen species (such as peroxynitrite, ONOO(-)) upon proteins. Higher levels (25 microM) of lactacystin did not further increase the levels of carbonyls, lipid peroxidation, 3-nitrotyrosine, or ubiquitinated proteins, but produced increases in the levels of 8-hydroxyguanine (a biomarker of oxidative DNA damage) and falls in levels of GSH. Lactacystin (25 microM) caused loss of viability, apparently by apoptosis, and also increased production of nitric oxide (NO.) (measured as levels of NO2- plus NO3-) by the cells; this was inhibited by N-nitro-L-arginine methyl ester (L-NAME), which also decreased cell death induced by 25 microM lactacystin and decreased levels of 3-nitrotyrosine. The NO. production appeared to involve nNOS; iNOS or eNOS were not detectable in either cell type. Another proteasome inhibitor, epoxomicin, had similar effects.
Acetylcysteine↗
Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative stress and cell death induced by hydrogen peroxide, 4-hydroxynonenal or serum deprivation: potentiation of injury by ALS-related mutant superoxide dismutases and protection by Bcl-2.
Mutations in Cu/Zn-superoxide dismutase (SOD1) are associated with some cases of familial amyotrophic lateral sclerosis (ALS). We overexpressed Bcl-2, wild-type SOD1 or mutant SOD1s (G37R and G85R) in NT-2 and SK-N-MC cells. Overexpression of Bcl-2 rendered cells more resistant to apoptosis induced by serum withdrawal, H2O2 or 4-hydroxy-2-trans-nonenal (HNE). Overexpression of Bcl-2 had little effect on levels of protein carbonyls, lipid peroxidation, 8-hydroxyguanine (8-OHG) or 3-nitrotyrosine. Serum withdrawal or H2O2 raised levels of protein carbonyls, lipid peroxidation, 8-OHG and 3-nitrotyrosine, changes that were attenuated in cells overexpressing Bcl-2. Overexpression of either SOD1 mutant tended to increase levels of lipid peroxidation, protein carbonyls, and 3-nitrotyrosine and accelerated viability loss induced by serum withdrawal, H2O2 or HNE, accompanied by greater rises in oxidative damage parameters. The effects of mutant SOD1s were attenuated by Bcl-2. By contrast, expression of wild-type SOD1 rendered cells more resistant to loss of viability induced by serum deprivation, HNE or H2O2. The levels of lipid peroxidation in wild-type SOD1 transfectants were elevated. Overexpression of mutant SOD1s makes cells more predisposed to undergo apoptosis in response to several insults. Our cellular systems appear to mimic events in patients with ALS or transgenic mice overexpressing mutant SOD1.
Aldehydes↗
6-hydroxydopamine increases the hydroxylation and nitration of phenylalanine in vivo: implication of peroxynitrite formation.
In the present study, we investigated the effect of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) on hydroxyl free radical and peroxynitrite formation in vivo using D-phenylalanine as a novel mechanistic probe. In vivo microdialysis was carried out in the striatum of freely moving male Wistar rats. The microdialysis probes were perfused with artificial cerebrospinal fluid containing 5 mM D-phenylalanine (flow rate 2 microL/min). After obtaining a stable baseline 6-OHDA was delivered into the striatum via reverse microdialysis for 60 min. HPLC measurements of the effluent were performed using photodiode array detection for determination of phenylalanine derived o-tyrosine and m-tyrosine (as hydroxylation markers) as well as of nitrotyrosine and nitrophenylalanine (as nitration markers). The basal levels of the hydroxylation derived products of phenylalanine were approximately 100-fold higher than those of the nitration derived products. 6-OHDA (0.1, 1, 10 mM) significantly increased o- and m-tyrosine up to nine- and 13-fold, respectively, whereas levels of 3-nitrotyrosine and 4-nitrophenylalanine were significantly increased up to 422- and 358-fold, respectively. The results demonstrate that phenylalanine is a sensitive in vivo marker for 6-OHDA-induced hydroxylation and nitration reactions which are clearly concentration dependent. We conclude that peroxynitrite formation is involved in 6-OHDA-induced neurochemical effects.
Adrenergic Agents↗
In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimer's disease.
Salvia lavandulaefolia Vahl. (Spanish sage) essential oil and individual monoterpenoid constituents have been shown to inhibit the enzyme acetylcholinesterase in-vitro and in-vivo. This activity is relevant to the treatment of Alzheimer's disease, since anticholinesterase drugs are currently the only drugs available to treat Alzheimer's disease. Other activities relevant to Alzheimer's disease include antioxidant, anti-inflammatory and estrogenic effects. Results of in-vitro tests for these activities are reported here for S. lavandulaefolia extracts, the essential oil and its major constituents. Antioxidant activity (inhibition of bovine brain liposome peroxidation) was found in the EtOH extract of the dried herb (5 mg mL(-1)) and the monoterpenoids (0.1 M) alpha- and beta-pinene and 1,8-cineole. Thujone and geraniol had lower antioxidant effects, while camphor had no antioxidant effects. Possible anti-inflammatory activity (eicosanoid inhibition in rat leucocytes) was found in the EtOH extract (50 microg mL(-1)) and was shown by the monoterpenoids alpha-pinene and geraniol (0.2 mM), but not 1,8-cineole, thujone or camphor. Possible estrogenic activity (via induction of beta-galactosidase activity in yeast cells) was found in the essential oil (0.01 mg mL(-1)) and the monoterpenoid geraniol (0.1-2 mM). 1,8-Cineole, alpha- and beta-pinene and thujone did not exhibit estrogenic activity in this analysis. These results demonstrate that S. lavandulaefolia, its essential oil and some chemical constituents have properties relevant to the treatment of Alzheimer's disease and provide further data supporting the value of carrying out clinical studies in patients with Alzheimer's disease using this plant species.
Alzheimer Disease↗
Glial cells and abnormal protein handling in the pathogenesis of Parkinson's disease.
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Humans↗
Expression and distribution of CYP2C enzymes in rat basal ganglia.
The function and integrity of the basal ganglia is modulated by sex steroids whose activity may be controlled by P450 enzymes, such as members of the CYP2C subfamily. The expression of CYP2C enzymes in rat basal ganglia was examined by immunohistochemistry along with some of the factors that might control their expression. Whereas no CYP2C11 or CYP2C12 immunoreactivity was detected in the basal ganglia of either male or female rats, marked CYP2C13 immunoreactivity was evident in neurones of the subthalamic nucleus, substantia nigra, and interpeduncular nucleus. Strong CYP2C13 immunoreactivity was also expressed in the cortex, olfactory tubercle, hippocampus, dentate gyrus, hypothalamic nuclei, medial habenular nucleus, red nucleus, and medial forebrain bundle. Similar results were found in male and female rats. Following 6-hydroxydopamine lesioning of the nigro-striatal tract, tyrosine hydroxylase immunoreactivity was absent and CYP2C13 immunoreactivity was decreased markedly in the substantia nigra pars compacta, implying its presence in dopaminergic neurones. Modulation of sex steroids, using castrated rats, had no effect on the number of CYP2C13 positive neurones in the substantia nigra pars compacta. These results indicate that CYP2C13 protein is constitutively and widely expressed in rat brain. However, its expression is not sex-specific and is unaffected by castration. The role of CYP2C13 in brain is unknown but it may be involved in the generation of neurosteroids and catecholoestrogens.
Animals↗
Extracellular accumulation of nitric oxide, hydrogen peroxide, and glutamate in astrocytic cultures following glutathione depletion, complex I inhibition, and/or lipopolysaccharide-induced activation.
Dopaminergic neuronal death in substantia nigra in Parkinson's disease is accompanied by depletion of reduced glutathione levels and inhibition of complex I activity which occur partially in normal or activated cells. The relationship between neuronal death and altered glial function is not known, but this may involve the release of toxic mediators from astrocytes and microglia, which in turn cause neuronal injury. We have examined the effects of (l)-buthionine-[S,R]-sulfoximine ((l)-BSO)-induced glutathione depletion, inhibition of complex I activity by 1-methyl-4-phenylpyridinium (MPR(+)), and/or lipopolysaccharide (LPS)-induced activation on the extracellular accumulation of nitric oxide (NO), hydrogen peroxide (H(2)O(2)), and glutamate in primary cultures of rat forebrain astrocytes. Depletion of glutathione levels by up to 90% did not alter NO, H(2)O(2), or glutamate levels in cultured astrocytes. Inhibition of complex I activity by up to 43% had no effect on extracellular NO accumulation, but increased H(2)O(2) and glutamate levels. LPS-induced activation of cultured astrocytes increased extracellular levels of NO, H(2)O(2), and glutamate. Extracellular accumulation of NO and H(2)O(2) caused by LPS was markedly less in glutathione-depleted or complex I-inhibited astrocytic cultures compared to normal astrocytic cultures. In conclusion, complex I inhibition or activation of glial cells, alone or in combination with glutathione depletion, results in the extracellular accumulation of glutamate and the formation of NO and H(2)O(2), which in turn may form highly toxic peroxynitrite and hydroxyl radicals. Thus, altered glial function leading to oxidative stress and excitotoxicity may contribute to the initiation or progression of neuronal death in substantia nigra in Parkinson's disease.
1-Methyl-4-phenylpyridinium↗
Adenosine A(2A) receptor mRNA expression in Parkinson's disease.
The expression of the human adenosine A(2A) receptor was examined by reverse transcription polymerase chain reaction in post-mortem human brain tissue that was obtained from normal subjects and patients who died with Parkinson's disease. Adenosine A(2A) receptor mRNA was detected in both striatal (nucleus accumbens, caudate nucleus and putamen) and extrastriatal (globus pallidus and substantia nigra) brain regions. A significant decrease in the level of adenosine A(2A) receptor mRNA was found in the anterior and posterior caudate nucleus and anterior dorsal putamen, whereas a significant increase was observed in the substantia nigra pars reticulata of Parkinsonian brain when compared to age-matched controls. No change in adenosine A(2A) receptor mRNA levels was seen in any other brain region examined. This study demonstrates that A(2A) receptor mRNA expression is altered in the basal ganglia of patients who died with Parkinson's disease and who were receiving treatment with dopaminergic drugs. The adenosine A(2A) receptor appears subject to regulation by dopaminergic systems in human brain, though these data do not permit a distinction to be made between the effects of neuronal degeneration or drug treatment. The adenosine A(2A) receptor may therefore form a target for the treatment of basal ganglia disease.
Aged↗
CuZn-superoxide dismutase transgenic mice: no effect on longevity, locomotor activity and 3H-mazindol and 3H-spiperone binding over 19 months.
This study was designed to determine whether CuZn-superoxide dismutase (SOD) is neuroprotective against aging in the nigrostriatal tract. Twenty-four male mice transgenic for human CuZnSOD, resulting in overexpression of the cytosolic enzyme, were compared with 11 matched controls over 19 months. There was no difference in longevity, locomotor activity, or 3H-mazindol or 3H-spiperone binding in the nigrostriatal tract in the two groups. Thus there was no evidence that increased CuZnSOD was neuroprotective in this model.
Animals↗
Dysfunction of rat forebrain astrocytes in culture alters cytokine and neurotrophic factor release.
Altered glial cell function occurring in substantia nigra in Parkinson' disease may lead to the release of cytokines and impairment of neurotrophic factor production, which in turn, may cause dopaminergic apoptosis. To evaluate this concept, primary cultures of rat brain astrocytes were activated with lipopolysaccharide (LPS), depleted of glutathione with L-buthionine-[S,R]-sulfoximine or subjected to complex I inhibition with 1-methyl-4-phenylpyridinium. The effects on tumour necrosis factor-alpha (TNF-alpha) release, dopamine-stimulated glial cell line derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) release were determined. LPS activation or inhibition complex I activity, but not glutathione depletion, stimulated TNF-alpha release. Glutathione depletion or complex I inhibition, but not LPS-induced activation, impaired dopamine-stimulated GDNF release. None of these treatments altered BDNF release. Thus, altered glial function leading to TNF-alpha-mediated or GDNF withdrawal-induced dopaminergic apoptosis may contribute to nigral degeneration in Parkinson's disease.
Adaptor Proteins, Vesicular Transport↗
The copper transport protein Atox1 promotes neuronal survival.
Atox1, a copper transport protein, was recently identified as a copper-dependent suppressor of oxidative damage in yeast lacking superoxide dismutase. We have previously reported that Atox1 in the rat brain is primarily expressed in neurons, with the highest levels in distinct neuronal subtypes that are characterized by their high levels of metal, like copper, iron, and zinc. In this report, we have transfected the Atox1 gene into several neuronal cell lines to increase the endogenous level of Atox1 expression and have demonstrated that, under conditions of serum starvation and oxidative injury, the transfected neurons are significantly protected against this stress. This level of protection is comparable with the level of protection seen with copper/zinc superoxide dismutase and the anti-apoptotic gene bcl-2 that had been similarly transfected. Furthermore, neuronal cell lines transfected with a mutant Atox1 gene, where the copper binding domain has been modified to prevent metal binding, do not afford protection against serum starvation resulting in apoptosis. Therefore, Atox1 is a component of the cellular pathways used for protection against oxidative stress.
Amino Acid Sequence↗