- Email: [email protected]
Redox metals and neu rodegenerative disease
220
Redox metals and neurodegenerative Lawrence Multiple metals
M Sayre *, George
Perrytand
lines of evidence implicate redox-active transition as mediators of oxidative stress in neurodegenerative
diseases.
Among
that transition
the recent
metals
neurodegeneration, binding in the latter
bind
research
discoveries
is the finding
to proteins
associated
with
including the prion protein. Whereas case may serve an antioxidant function,
adventitious binding of metals to other proteins appears to preserve their catalytic redox activity in a manner that disturbs free radical iron-containing reduced
homeostasis. Alterations in the levels of copperand metalloenzymes, involved in processing partially
oxygen
redox balance even in familial mutations
species,
are also
in neurodegenerative forms of amyotrophic
in superoxide
dismutase,
likely
to contribute
to altered
diseases. Nonetheless, lateral sclerosis linked it is unclear
whether
to
an
altered enzyme activity or, indirectly, a disturbance in transitionmetal homeostasis is involved in the disease pathogenesis. Addresses Departments of *Chemistry and tPathology, University, Cleveland, OH 44106, USA *e-mail: [email protected] Current
Opinion
inChemical
Biology
1999,
Case Western
Reserve
Science
Ltd ISSN
Mark A Smith? between biochemical processes leading to production of reactive oxygen species (ROS) and the cellular antioxidant cascade, causes molecular damage that can lead to a critical failure of biological functions and ultimately cell death. All aerobic organisms produce at least minimal levels of ROS, mostly arising from the side-production of superoxide during the reduction of molecular oxygen by mitochondria. That oxidative stress has been frequently implicated in neurodegeneration (reviewed in [l]) reflects the selective vulnerability of the central nervous system arising from increased diooxygen utilization. Additionally, H,O,, produced by oxidases such as monoamine oxidase, can result in greater oxidative stress susceptibility in tissues enriched in these enzymes. In recent years, the explosion of research on the role of nitric oxide (NO) in neurotransmission and signaling has resulted in recognition of ‘nitrosative stress’, a form of oxidative stress that is directly tied to the reaction of superoxide with NO to give peroxynitrite. Peroxynitrite is capable of both oxidation chemisty and nitration of the aromatic sidechains of tyrosine and tryptophan.
3:220-225
http://biomednet.com/elecref/1367593100300220 Q Elsevier
disease
1367-5931
Abbreviations amyloid-P AP AD Alzheimer’s disease ALS amyotrophic lateral sclerosis P-protein precursor w CP ceruloplasmin Ft ferritin IRP iron regulatory protein NFT neurofibrillaty tangles PD Parkinson’s disease reactive oxygen species ROS superoxide dismutase SOD SP senile plaques Tf transferrin
The principal ROS culprit of oxidative stress is the hydroxyl radical, which inflicts damage to biomacromolecules at diffusion-controlled rates (i.e. within nanometer distances from its site of generation). Although peroxynitrite also appears capable of hydroxyl radical-like activity, most hydroxyl radicals reflect the Fenton reaction between reduced transition metals (usually iron[II] or copper[I]) and H,O,. Re-reduction of the resulting oxidized transition metal ions (iron[III] or copper[II]) can be effected by superoxide or by other available cellular reductants such as vitamin C. In addition to their redox role, transition metals, along with redox-inactive metal ions, may contribute to neurodegeneration through their deleterious effects on protein and peptide structure, such as a pathological aggregation phenomenon. In these cases, transition metals can sometimes exert dual neurotoxic properties.
Introduction There is substantial interest in the role of copper, manganese, iron and other trace redox-active transition metals in the neuropathology of neurodegenerative disorders such as Parkinson’s disease (PD), AIzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). These metals are essential in most biological reactions (e.g. in the synthesis of DNA, RNA and proteins), and as cofactors of numerous enzymes, particular those involved in respiration; thus, their deficiency can lead to disturbances in central nervous system and other organ function. However, excessive tissue accumulation of redox-active transition metals can be cytotoxic, in particular because perturbations in metal homeostasis result in an array of cellular disturbances characterized by oxidative stress and increased free radical production. Oxidative stress, defined as the imbalance
Opposing oxidant damage is an array of antioxidant defenses that, in mammalian cells, include both enzymatic and nonenzymatic entities. Cytosolic copper-zinc superoxide dismutase (CuZnSOD) and mitochondrial manganese superoxide dismutase (MnSOD), which convert superoxide to 0, and H,O,, are important in enzymatic defences. H202 is removed by catalase and peroxidases, which have ubiquitous tissue distribution. The scope of this review is to evaluate recently published work that implicates redox-active transition-metal ions in oxidative stress contributing to neurodegeneration. The review will &icus not anly on roles of metalloenzymes implicated in oxidative stress and the a&.orp of adventitious ‘free’ trace metal ions, but also on metal-ion transport and storage
Redox
proteins closely tied to iron and copper homeostasis. Also, proteins not normally functioning as metal-binding proteins may sometimes act as neuroprotectants by sequestering the metal ions in redox inactive forms or as neurotoxicants by binding metals in a manner which retains redox activity
Antioxidant enzymes and proteins transition-metal homeostasis
involved
in
The development of transgenic mouse ‘knockout’ and overexpression models has permitted a range of studies to critically evaluate the extent to which selected biological processes affect cell viability. For example, if one or the other of the SOD enzymes serve a crucial antioxidant function, then knockout animals may exhibit increased oxidative stress parameters. This oxidative stress may be global or may be localized to the cellular compartment normally protected by the specific SOD enzyme. In support of this notion, MnSOD knockout mice, suffering a 50% drop in mitochondrial SOD activity but no reduction of CuZnSOD or glutathione peroxidase activity, were found to exhibit increased oxidative damage to mitochondria, as shown by increased mitochondrial protein carbonyls and 8hydroxydeoxyguanosine in mitochondrial DNA [Z’]. In contrast, no damage to cytosolic proteins or to nuclear DNA was observed. Analysis of homozygote knockouts showed mitochondrial degeneration that could only be followed for the two weeks that these mice lived [3’]. These results suggest that decreases in MnSOD activity in VZUO can explain increased oxidative damage in mitochondria and alterations in essential mitochondrial function. In other studies, overexpression of human CuZnSOD in mice, resulting in a tenfold higher level in both myocytes and endothelial cells, was able to quench a burst of superoxide (in electron paramagnetic resonance detection) and reduce functional damage following 30 minutes global ischemia [4]. These results suggest that superoxide is an important factor in protecting against postischemic injury and it is therefore surprising that CuZnSOD knockout mice show little if any neurodegenerative phenotype [S”]. Nonetheless, it is apparent that decreases in CuZnSOD activity can lead to a perturbation of cellular antioxidant defense mechanisms to promote a pro-oxidant condition. So, while absences of CuZnSOD have little effect, enzyme inactivation by metalcatalyzed oxidation promotes oxidative damage [6]. These surprising differences, while seemingly paradoxical, may be particularly relevant to human diseases, as discussed later. Ceruloplasmin (CP), an important copper storage protein, is one of the key proteins that responds to oxidative stress. CP is considered the major Fe(II)-oxidizing enzyme in the CNS, and an inherited metabolic disorder called aceruloplasminemia is associated with an impairment in iron homeostasis and consequent neurodegeneration [7]. Interestingly, while CP is increased in brain tissue and cerebrospinal fluid in AD, PD and Huntington’s disease (I-ID) patients [8], neuronal levels of CP remain unchanged [9]. Therefore, while increased CP may indicate a compensatory response to increased oxidative
metals
and neurodegenerative
disease
Sayre, Perry and Smith 221
stress in AD, its failure to do so in neurons may play an important role in metal-catalyzed damage [9]. In fact, studies directed at clarifying the relationship between oxidative stress and tissue metal-ion levels indicate that both the ratio of copper to zinc and the levels of CP are significantly higher with increasing age, and higher yet in cases with neurodegeneration [lo]. Since the copper : zinc ratio is significantly correlated with systemic oxidative stress, (i.e. lipid peroxidation), these findings suggest that increased oxidarive stress burden in aging and neurodegeneration may reflect, in large part, copper-mediated ROS production. In this case, redox-inert zinc may serve as an antioxidant by preventing binding of pro-oxidant copper at tissue sites. A novel glycolipid-anchored membrane-bound form of CP expressed by astrocytes in the mammalian CNS was recently identified [ll’], and it will be of interest to determine whether this form has any role in the neurodegenerative process. The escalating interest in prion diseases, (e.g. Creutzfeldt-Jakob disease), apparently caused by infection with an altered prion protein conformation that is transferred to endogenous protein, begs the question as to the normal role of this cell-surface glycoprotein in healthy individuals. In this regard, several lines of evidence indicate that the prion protein binds Cu(I1) and thus, as with CP, may serve a cytoprotective role [12”,13]. One possible scenario, consistent with the finding in cell cultures that copper stimulates endocytosis of prion protein from the cell surface, is that prion protein controls copper metabolism by serving as a recycling receptor for uptake of extracellular copper [ 14”].
CuZnSOD mutations lateral sclerosis
and familial
amyotrophic
A crucial breakthrough in our understanding of ALS comes from the finding that many of the familial cases (FALS) are associated with one or another mutation in the CuZnSOD gene. The protein products of these mutations retain nearly identical SOD activity, but take on altered properties linked to oxidative stress, possibly involving a gain-of-function peroxidase activity [ 151. In this regard, transgenic mice overproducing a human FALS CuZnSOD mutant display increases in protein carbonyls suggestive of increased hydroxyl radical production or lipoxidation-derived radicals [16*]. Also, using in viva microdialysis, increased hydroxyl radical production in the striatum, as determined by conversion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid, was seen for mice overexpressing mutant CuZnSOD relative to mice overexpressing the wild type human enzyme [17’]. The hypothesis that mutant SOD-induced neurodegeneration is associated with disturbances in neuronal free-radical homeostasis is further supported by observations made on several neuronal cell cultures expressing the mutant SOD [18’]; however, the mechanism underlying the link between the SOD mutations and oxidative stress indicators appears not to be simply increased production of hydroxyl radicals. since no increases in HO adducts are seen in vitro for the Gly93+Ala and Ala4+Val mutants relative to wild type enzyme [ 191.
222
Bio-inorganic
chemistry
Recent studies have shown that the mutant and wild type SODS differ neither in the rates of superoxide dismutation nor in another enzyme diagnostic, namely H20z-mediated inactivation [20’,21]. Structural analysis of the mutant enzymes revealed in some cases, alterations such as subunit asymmetry that suggest aberrant copper-mediated redox chemistry stemming from less tight folding and thus a more open ‘active site’ [22’,23]. Thus, the gain-of-function activity may reflect a ‘rechanneling’ of the enzyme to oxidize biomolecules that normally would never gain access to the: SOD oxidative half-reaction. Alternatively, the mutant SOD may possess weakened affinities for zinc or copper leading to a fraction of enzyme with abnormal activity [ 191 or oxidative reactions associated with leakage of copper [ZO’]. For the predominant, sporadic form of ALS, an imbalance in trace metal ions, possibly tied to increased oxidative stress, has been considered for some time. Recent studies provide evidence for decreases in copper in cerebrospinal fluid and serum, and increases in manganese in serum relative to age-matched controls [24].
Iron in neurodegenerative
disease
Free iron, more than any other transition metal, has been implicated in undergoing redox transitions in viva with the consequential generation of oxygen free radicals, which can, in turn, induce tissue oxidative stress. Abnormally high levels of iron and oxidative stress have been demonstrated in a number of neurodegenerative disorders including AD [25”] and those characterized by nigral degeneration such as PD, multiple system atrophy and progressive supranuclear palsy. Since oxidative stress is usually associated with increased free iron, experimental findings of increased total iron do not necessarily implicate increased oxidative stress if there are concomitant increases in proteins that store iron in redox-inert forms. For example, ferritin (Ft; which may be upregulated in PD and AD) contains a core of insoluble, unreactive ferrihydrate. However, the entry and release of iron from Ft occurs via its more coordinatively labile ferrous state, active in Fenton generation of hydroxyl radicals. Microglia (macrophage-like cells in the central nervous system) are the major sites of Ft bound iron and are thought to be partly responsible for oxidative damage in PD and other neurodegenerative disorders. Microglia stimulated in vivo with phorbol ester show increased lipid peroxidation resulting from a superoxide-dependent release of iron from Ft [26]. Besides superoxide, ferritin iron can be releasedby 6-hydroxydopamine, a neurotoxin implicated in PD, and other easily oxidized catechols [27]. These studies suggest that Ft iron releasecontributes to free-radical-induced cell damage in Gvo via Fenton production of hydroxyl radicals. In addition, the interplay between oxidative stressand control of iron metabolism in the brain is exemplified by the finding of abnormal iron deposition associated with lipid peroxidation in a transgenie mouse model (expressing interleukin-6 in astrocytes) of a blood-brain barrier defect associatedwith progressive neurodegeneration [ZS].
In recent years, it has become evident that the regulation and management of iron at the cellular level, although primarily by the transferrin (Tf) receptor and Ft, is also under the control of the lactotransferrin receptor, melanotransferrin, CP and divalent cation transporter 1. Thus, disruption in the expression of these latter proteins in the brain also probably contributes to altered brain-iron metabolism of age-related neurodegenerative disorders such asPD, AD, HD and ALS [29’]. Overall regulation of cellular iron metabolism, involves the action of two iron regulatory proteins, IRP-1 and IRP-2. IRP-1, but not IRP-2, is rapidly activated by extracellular H,O,, establishing a regulatory connection between the control of iron metabolism and responseto oxidative stress. This activation has recently been recapitulated in aha, and shown not to occur directly, but to require the presence of a cellular membrane-associated component sensitive to temperature and alkaline phosphatase [30”]. Further studies in this area should lead to a more clear understanding of the causative link between iron-induced oxidative stress and neuronal death. Interestingly, IRPs show significant alterations in AD patients [31], paralleling alterations in redox-active iron [25”].
Iron-mediated oxidative stress substantia nigra in Parkinson’s
in the disease
Despite the recent identification of a mutation in the a-synuclein gene in certain casesof familial Parkinsonism, which may ultimately lead to an understanding of the biochemical mechanisms of selective dopaminergic cell death in these cases,the etiology of the diseaseremains undefined. Nonetheless, several biochemical abnormalities in PD brain tissue have been identified, including a mitochondrial complex I deficiency, oxidative stress and excessiron. Iron accumulates in astrocytes in the substantia nigra of old rats [32,33] and at the sametime there is an increase in the Fe(II1) : Fe(I1) ratio and a decrease in reduced glutathione [34]. One interpretation is that mitochondrial sequestration of redox-active iron in aging nigral astroglia may be one factor predisposing the senescent nervous system to Parkinsonism and other neurodegenerative disorders. In fact, a persistent condition of oxidative stressassociatedwith greatly perturbed intracellular redox equilibria is widely recognized as a pathogenetic factor underlying neurodegeneration. Moreover, there is circumstantial evidence that the intracellular redox imbalance results in aberrant oxidation of dopamine to 6-hydroxydopamine, which in turn can undergo autoxidation to the corresponding quinone concomitant with generation of superoxide. This reaction cascade, either by itself, or as amplified by redox cycling of this quinone leading to further generation of ROS at the expense of cellular reductants, can serve to explain the ultimate demise of these neurons. Studies to clarify the mechanism of dopamine oxidation in vitro have demonstrated conversion to 6-hydroxydopamine in the presence of Fe(H) and either H,OZ or alkyl peroxides [35].
Redox
The role of manganese
in Parkinson’s
disease
Chronic exposure to manganese results in extrapyramidal syndromes resembling PD, and manganese has therefore been labeled as an environmental toxic factor that induces brain dysfunction. One suggestion is that manganese acts as a dopaminergic neurotoxin, in the same manner as iron, by mediating the generation of ROS and the subsequent nonenzymatic autoxidation of dopamine to the neurotoxin 6-hydroxydopamine. There is no convincing in viva evidence for a pro-oxidant role of manganese in the brain, however. Also, the clinical picture of manganese-induced Parkinsonism is by no means clear, because there is conflicting evidence regarding whether it is selectively toxic to dopaminergic neurons. Additionally, recent findings suggest that manganese actually may act as an antioxidant rather than pro-oxidant [36]. In this study, Mn(I1) was found to protect, dose-dependently, against the toxicity of Fe(I1) administered intranigrally to rats. This protection could result from the fact that Mn(II), itself inactive in Fenton chemistry, competes with Fe(I1) in oxidative cascades. It thus appears that the Parkinsonian-like syndrome induced by chronic manganese poisoning may have little connection to nigrostriatal damage occurring in idiopathic PD.
Redox-active Alzheimer’s
transition disease
metals
in
AD is characterized pathologically by the presence of neurofibrillary tangles (NFT), senile plaques (SP), neuropil threads, amyloid-P (Afl) deposition, and a selective loss of neurons. Much excitement in recent years has come from the discovery of a multiplicity of mutations in the genes encoding the P-protein precursor (PPP) and/or the presenilins, which account for the bulk of the familial cases of AD on the basis of overproduction of PPP and/or altered PPP proteolytic processing, both leading to increased AP. Transgenic mice overproducing the human mutations have been shown to develop SP and some neurotoxicity, but the mechanism of this neurotoxicity may be unrelated to neuronal loss that occurs in AD, and no complete animal model for even familial AD exists. Moreover, the predominance of AD is sporadic. Of the various hypotheses that have been suggested for the etiology of sporadic AD, the one receiving most recent attention is a role for oxidative stress. Several studies have indicated imbalances of trace elements, including aluminiurn, silicon, lead, mercury, zinc, copper and iron. A disruption of homeostasis of copper and iron is particularly significant in light of substantial, recent evidence for increases in oxidative stress parameters such as lipid peroxidation, as well as increases in markers of oxidative damage to both the protein constituents of the pathological hallmark structures of AD (NFT and SP) [37,38*,39,40*] and nucleic acids [41”]. Using microparticle-induced X-ray ly found that Zn(II), Fe(II1) and elevated in AD neuropil and that cantly further concentrated within
emission, it was recentCu(I1) are significantly these metals are signifithe core and periphery
metals
and neurodegenerative
disease
Sayre,
Perry and Smith
223
of senile plaques [42’]. These results extend earlier studies reporting increased levels of iron, Tf and Ft in AD. Using an in sitti iron detection method, we found a marked association of redox-active iron with both NFT and SP in AD [ZS”]. The association of iron with NFT may be, in part, related to iron binding to their primary protein constituent, z [43]. At the same time, as discussed earlier, whereas IRP-1 was found to be present in similar levels in both AD and control brain tissue, IRP-2 co-localized with redox-active iron in NFT, SP neurites, and neuropil threads [31]. These results suggest that alterations in IRP-2 may be directly linked to impaired iron homeostasis in AD. In recent histochemical studies, we found that redox activity of the lesions in AD can be detected directly, can be inhibited by prior exposure of tissue sections to copper- and iron-selective chelators, and can be reinstated following reexposure of the chelator-treated sections to either copper or iron salts (LM Sayre and co-workers, unpublished data). Our studies indicating the presence of redox-active iron and probably also copper in AD pathology suggest that these metal accumulations are major producers of the ROS responsible not only for the numerous oxidative stress markers that appear on NFT and SP, but also for the more global oxidative stress parameters observed in AD. Other studies of oxidative stress in AD have focused on the inducible mitochondrial MnSOD and the constitutive cytoplasmic CuZnSOD enzymes. The CuZnSOD gene is associated with AD neuropathology, and levels of both MnSOD mRNA and CuZnSOD were found to be increased in AD, whereas the total antioxidant status was decreased [44]. However, since SOD enzymes are key components of the cellular antioxidant armementarium, any pro-oxidant mechanism linked to SOD must derive from the balance in the local concentrations of superoxide and H,O,, which together can produce the hydroxyl radical by the Haber-Weiss process.
The role of metal ions in the aggregation Ap and @PP/Aplinked reactive oxygen species production
of
Evidence for an imbalance of trace-metal homeostasis in AD have led, over the years, to efforts to identify possible effects of metal ions on the aggregation of A& For example, it was found that aluminium, iron and zinc but not calcium, cobalt, manganese, copper, magnesium, sodium or potassium accelerated aggregation of AP [45]. More recent studies, however, suggest that the aggregatory effect of metals depends critically on the pH. It was found that Cu(I1) induced aggregation of A@ l-40) when the pH was lowered from 7.4 to 6.8, a phenomenon that was not common to other metals tested [46’]. ,4 mildly acidic environment, together with increased Zn(I1) and Cu(II), are common features of inflammation associated with increased oxidative damage stemming from microglial-derived peroxynitrite. The association of Cu(II), Zn(I1) and Fe(I1) with A@ seen in a& could explain the enrichment of these metals with SP in AD.
224
Bio-inorganic
chemistry
It is interesting to note in these studies on Afi aggregation that the effect of the transition metal is not purported to involve a redox role. This contrasts with other results suggesting a synergistic action of AD and copper or iron in mediating ROS production [47]. Also, Cu(II) binds to PPP and appears to be reduced to Cu(1) concomitant with production of a disulfide linkage [48). Subsequent exposure to H,O, results in reoxidation of Cu(1) and concomitant sitespecific cleavage of J3PP Redox chemistry associated with AD- or PPP-bound metals could contribute to a perturbation of free-radical homeostasis.
Over the past year or so, there has been an increasing awareness of the seminal role that redox-active transition metals play in a variety of neurodegenerative diseases. The stage is now set to critically examine the importance of these basic research findings as they are translated into therapeutic modalities such as antioxidants and chelating agents that are being used clinically. The next two to three years will be truly fascinating to watch unravel.
Papers of particular have been highlighted l
**of 1.
laboratories is supported the Alzheimer’s Association
and recommended interest, as:
published
within
reading the annual
period
of review,
of special interest outstanding interest Smith MA, Sayre LM, Perry G: Primary involvement of oxidative damage and redox imbalance in Alzheimer and other neurodegenerative diseases. In Redox Regulation of Cell Signaling. Edited by Packer L, Yodoi J. New York: Marcel Dekker, Inc; 1988:115-126.
Melov S, Schneider Crapo JD, Wallace lacking mitochondrial Genef 1998,18:159-l This paper describes a mutase knockout mice tion. Mice die within two
JA, Day BJ, Hinerfeld D, Coskun P, Mirra SS, DC: A novel neurological phenotype in mice manganese superoxide dismutase. Nat 63. morphological study of manganese superoxide disshowing mitochondrial welling and axonal vacuolaweeks of birth.
Wang P, Chen H, Qin H, Sankarapandi S, Becher MW, Wong PC, Zweier JL: Overexpression of human copper, zinc-superoxide dismutase (SOD1 1 prevents postischemic injury. Proc Nat/ Acad SC; USA 1998, 95:4556-4560.
5. ..
Bruijn LI, Houseweari MK, Kato S, Anderson KL, Anderson SD, Ohama E, Reaume AG, Scott RW, Cleveland DW: Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type 5001. Science 1998, 281 :1851-l 854. In addition to showing, as many previous studies have, that mutant Cu-Zn superoxide dismutase is associated with neurodegenerative damage, the knockout of this enzyme is shown to have no obvious neurodegenerative phenotype. 6.
9.
Castellani RJ, Smith MA, Nunomura A, Harris PLR, Perry G: Is increased redox-active iron in Alzheimer disease a failure of the copperbinding protein ceruloplasmin? Free Radical Biol A&d 1999, in press,
10.
Meuetti A, Pierdomenico Cuccurullo F, lmbastaro Fellin R: Copper/zinc aging and aging-related Med 1998, 25:676-681,
SD, Costantini T, Riario-Sforza ratio and systemic degenerative
AJ,
F, Roman0 F, De Cesare D, G, Di Giacomo F, Zuliani G, oxidant load: effect of diseases. Free Radical Biol
Pate1 BN, David S: A novel glycosylphosphatidylinositol-anchored from of ceruloplasmin is expressed by mammalian astrocytes. J Biol Chem 1997, 272:20 185-20190. A novel membrane-bound form of ceruloplasmin (CP) expressed by astrocytes in the mammalian CNS is reported. In the liver, CP is the major Fe(ll)-oxidizing enzyme, and this could be the same role for the CP in the CNS, as appears to be the case in aceruloplasminemia. Lack of this form could contribute to neuronal degeneration in Parkinson’s disease and Alzheimer’s disease. 12. ..
Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Truck T, von Bohlen A, Schulz-Schaeffer W et a/.: The cellular prion protein binds copper in viva. Nature 1997,390:684-687. The normal cellular form of prion protein binds Cu(ll) nearly as strongly does serum albumin. Thus, binding of Cu(ll) to prion protein may indicate cytoprotective role of this protein. Brown survival 1998,
DR, Schmidt B, Kretzschmar of prion protein knockout 70:1686-l 693.
as a
HA: Effects of copper on neurons and glia. J Neurochem
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Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardon A: Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 1998, 273:2851 O-2851 5. Manganese superoxide dismutase (MnSOD) knockout mice, exhibiting a 50% drop in mitochondrial activity of MnSOD but not CuZnSOD or glutathione peroxidase, witness an increased oxidative damage to mitochondria as shown by increased mitochondrial protein carbonyls and 8-hydroxydeoxyguanosine in mitochondrial DNA. No damage to cytosolic proteins or to nuclear DNA was observed.
4.
an inherited homeostasis.
Loeffler DA, LeWitl PA, Juneau PL, Sima AA, Nguyen HU, DeMaggio Bridunan CM, Brewer GJ, Dick RD, Troyer MD, Kanaley L: Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders Brain Res 1996, 738:265-274.
by grants from the Kational and the American Health
2. .
3. .
of iron
8.
13.
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Redox
metals
35
and
neurodegenerative
k%~?ei~d&
dk%d
disease
bt, &pTih%ITU~,
Sayre,
Perry
i%WdCd~,
Red
71~~~~~,~iiur~~tt7~u#n,~tyLi~~inr quinone by reaction of fatty acid hydroperoxides possible contributory mechanism for neuronal Parkinson’s disease. J Med Chem 1997,40:221 21.
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I: The familial amino acid substitutions the rate of inactivation dismutase by H,O,.
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KL, Maywald M, Schmittel M, Rlederer P, Gerlach M: In vitro of ferritin iron release and neurotoxicity. I Neurochem 70:2492-2499.
Smith MA, Harris PLR, Sayre LM, Beckman JS, peroxynitrite-mediated damage in Alzheimer’s 1997,17:2653-2657. Neurotlbnllary tangle-contalnmg neurons as well as pocampal neurons in Alzheimer disease, but not in cation by peroxymtrite in the form of protein tyrosine
C&an ZM, Wang 0: Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders. Brain Res Rev 1998, 27:257-267. . Abnormally high levels ot Iron and oxldatlve stress have been demonstrated in a number of neurodegenerative disorders, but there is no general agreement as to the causative link between iron-induced oxidative stress and neuronal death. Regulation/management of iron at the cellular level is primarily by the transferrln receptor and ferntin, but recent focus on the roles of the lactotransferrin receptor, melanotransferrin, ceruloplasmin, and divalent cation transporter, suggest that disruption in the expresston of these proteins in the brain is probably one of the important causes of altered brain iron metabolism of age-related neurodegenerative disorders such as Parkinson’s, Alzheimer’s and Huntington’s diseases and amyotrophic lateral sclerosis. Pantopoulos K, Hentze MW: Activation of iron regulatory protein-l by oxidative stress in vitro. Proc Nat/ Acad Sci USA 1998, 95:10559-10563. Iron regulatory protein-l (IRP-I), but not IRP-2, is rapidly activated by extracellular H,O, to bind iron-responsive elements on mRNA. Characterization of activation in ntro revealed that it does not occur directly, but requires the presence of a cellular membrane-associated component sensitive to temperature and alkaline phosphatase. SL, Connor protein
32.
Schipper Neurobiol
and
33.
Schlpper HM, Vlninsky R, Brull R, Small L, Brawer JR: Astroctye mitochondria: a substrate for iron deposition in the aging rat substantia nigra. fxp Neural 1998, 152:168-i 96.
34.
HM: Astrocytes, Aging 1996,
brain aging, 17:467-480.
Riederer P, Sofic E, Rausch W-D, Schmidt Youdim MBH: Transition metals, ferritin, acid in parkinsonian brains. J Neurochem
JR, Perry G: (IRP) in Alzheimer
neurodegeneration.
B, Reynold GP, Jellinger glutathione, and ascorbic 1989, 52:515-520.
end
Perry G: Widespread disease. J Neurosci apparently controls, nitration.
normal hipexhibit modifi-
Smith MA. Savre LM. Anderson VE. Harris PLR. Beal MF. Kowall N. Perry G: Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with dinitrophenylhydrazine. J Histochem Cytochem 1998,46:731-735.
Sayre LM, Zelasko DA, Harris PLR, Perry G, Salomon RG, Smith MA: 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 1997, 68:2092-2097. Antibodles selective for the stable, advanced 2-pentylpyrrole modification of protein lysines by 4-hydroxynonenal stain neurofibrillatory tangles (NFT-containing neurons, extracellular NFT, as well as apparently normal neurons in Alzheimer disease cases but not in controls. 41. .
Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA: RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer disease. J Neurosci 1999, in press. Oxidatlve damage to nucleic acids, leading to &hydroxyguanosine (8.OHG), primarily Involves cytoplasmtc RNA in vulnerable neurons. Neurons with neurofibrillary tangles show reduced damage. The restriction of damage to the cytosol suggests the source of 8-OHG is from metal-dependent formation of the hydroxyl radical.
l
Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR: Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neural Sci 1998, 158:47-52. Using microparticleinduced X-ray emission, Zn(ll), Fe(lll) and Cu(ll) were found to be significantly elevated in Alzhelmer’s disease neuropil. These metals are significantly further concentrated within the core and periphery of plaque deposits. 43.
K,
Perez M, Valpuesta JM, de Garcinl EM, Cluintana C, Arrasate M. Looez Carrascosa JL. Rabano A. Garcia de Yebenes Avila J: Ferritii is associated with the aberrant tau filaments present in progressive supranuclear palsy. Am J fathol 1998, 152:1531-1539.
44.
De Leo ME, Borrello S, Passantmo M, Palazzotti 6, Mordente A, Daniele A, Fillppmi V, Galeotta T, Masullo C: Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer’s disease. Neurosci Lett 1998, 250:173-l 76.
45.
Mantyh PW, Ghilardi JR, Rogers S, DeMaster E, Allen CJ, Stimson ER. Maaaio JE: Aluminum. iron. and zinc ions oromote aggregation of physiological concentrations of beta-amyloid peptide. J Neurochem 1993,61 :I 171-l 174.
30. ..
Smith MA, Wehr K, Harris PLR, Siedlak Abnormal localization of iron regulatory disease. Brain Res 1998, 788:232-236.
CC: from
42. .
29. .
31.
Taneda S, Richey PL, Miyata S, Yan S-D, Stern D, Monnier VM, Perry G: Advanced Maillard reaction are associated with Alzheimer disease pathology. Acad Sci USA 1994, 91571 O-571 4.
a
40. .
75.
26.
with dopamine: degeneration in I-221 6.
37.
38. .
225
i?-h~~
Sziraki I, Mohanakumar KP. Rauhala P. Kim HG. Yeh KJ. Chiueh Manganese: a transition metal protects nigrostriatai neurons oxidative stress in the iron-induced animal model of Parkinsonism. Neuroscience 1998, 85:1101-l 1 11.
Corson LB, Strain JJ, Culotta VC, Cleveland DW: Chaperonefaciliated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants. froc Nat/ Acad Sci USA 1998, 956361-6366. An analysis of a broad range of Cu,Zn-superoxide dismutase (SOD) mutants in Saccharomyces cerevisiae was carried out: all appear to bind copper and scavenge superoxide in viva. These results support a mechanism of SOD1 mutant-mediated disease arising from aberrant copper-mediated chemistry catalyzed by less tightly folded (and less constrained) mutant enzymes. All mutants acquire copper m viva via action of the copper chaperone for SOD1
T, Kakami A, alterations in Sci 1997, 147:171-l
Smith
36.
22. .
JS,
and
J.
II
46. .
Atwood CS, Motr RD, Huang X, Scarpa RC, Bacarra NME, Romano DM, Hartshorn MA, Tanzl RE, Bush Al: Dramatic aggregation of Altzheimer Aj3 by Cu(lI) is induced by conditions representing physiological acidosis. J Viol Chem 1998, 273:12817-l 2826. Cu(ll) induces aggregation of amyloid p peptlde (residues I-40) (AD [I -401) with slight lowering of pH. This may be a response to local injury. Association of metal with Afl(l-40) may explain the reported enrichment of Cu(ll), Zn(ll) and Fe(lll) with amyloid plaques in Alzheimer’s disease. 47.
Bondy SC, Guo-Ross SX, Truong AT: Promotion metal-induced reactive oxygen species formation Brain Res 1998. 799:91-96.
48.
Multhaup Masters undergoes hydrogen
of transition by p-amyloid.
G, Ruppert T, Schlicksupp A, Hesse L, Bill E, Pipkorn R, CL, Beyreuther K: Copper-binding amyloid precursor a site-specific fragmentation in the reduction of peroxide. Biochemistry 1998, 37:7224-7230.
Redox metals and neurodegenerative Lawrence Multiple metals
M Sayre *, George
Perrytand
lines of evidence implicate redox-active transition as mediators of oxidative stress in neurodegenerative
diseases.
Among
that transition
the recent
metals
neurodegeneration, binding in the latter
bind
research
discoveries
is the finding
to proteins
associated
with
including the prion protein. Whereas case may serve an antioxidant function,
adventitious binding of metals to other proteins appears to preserve their catalytic redox activity in a manner that disturbs free radical iron-containing reduced
homeostasis. Alterations in the levels of copperand metalloenzymes, involved in processing partially
oxygen
redox balance even in familial mutations
species,
are also
in neurodegenerative forms of amyotrophic
in superoxide
dismutase,
likely
to contribute
to altered
diseases. Nonetheless, lateral sclerosis linked it is unclear
whether
to
an
altered enzyme activity or, indirectly, a disturbance in transitionmetal homeostasis is involved in the disease pathogenesis. Addresses Departments of *Chemistry and tPathology, University, Cleveland, OH 44106, USA *e-mail: [email protected] Current
Opinion
inChemical
Biology
1999,
Case Western
Reserve
Science
Ltd ISSN
Mark A Smith? between biochemical processes leading to production of reactive oxygen species (ROS) and the cellular antioxidant cascade, causes molecular damage that can lead to a critical failure of biological functions and ultimately cell death. All aerobic organisms produce at least minimal levels of ROS, mostly arising from the side-production of superoxide during the reduction of molecular oxygen by mitochondria. That oxidative stress has been frequently implicated in neurodegeneration (reviewed in [l]) reflects the selective vulnerability of the central nervous system arising from increased diooxygen utilization. Additionally, H,O,, produced by oxidases such as monoamine oxidase, can result in greater oxidative stress susceptibility in tissues enriched in these enzymes. In recent years, the explosion of research on the role of nitric oxide (NO) in neurotransmission and signaling has resulted in recognition of ‘nitrosative stress’, a form of oxidative stress that is directly tied to the reaction of superoxide with NO to give peroxynitrite. Peroxynitrite is capable of both oxidation chemisty and nitration of the aromatic sidechains of tyrosine and tryptophan.
3:220-225
http://biomednet.com/elecref/1367593100300220 Q Elsevier
disease
1367-5931
Abbreviations amyloid-P AP AD Alzheimer’s disease ALS amyotrophic lateral sclerosis P-protein precursor w CP ceruloplasmin Ft ferritin IRP iron regulatory protein NFT neurofibrillaty tangles PD Parkinson’s disease reactive oxygen species ROS superoxide dismutase SOD SP senile plaques Tf transferrin
The principal ROS culprit of oxidative stress is the hydroxyl radical, which inflicts damage to biomacromolecules at diffusion-controlled rates (i.e. within nanometer distances from its site of generation). Although peroxynitrite also appears capable of hydroxyl radical-like activity, most hydroxyl radicals reflect the Fenton reaction between reduced transition metals (usually iron[II] or copper[I]) and H,O,. Re-reduction of the resulting oxidized transition metal ions (iron[III] or copper[II]) can be effected by superoxide or by other available cellular reductants such as vitamin C. In addition to their redox role, transition metals, along with redox-inactive metal ions, may contribute to neurodegeneration through their deleterious effects on protein and peptide structure, such as a pathological aggregation phenomenon. In these cases, transition metals can sometimes exert dual neurotoxic properties.
Introduction There is substantial interest in the role of copper, manganese, iron and other trace redox-active transition metals in the neuropathology of neurodegenerative disorders such as Parkinson’s disease (PD), AIzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). These metals are essential in most biological reactions (e.g. in the synthesis of DNA, RNA and proteins), and as cofactors of numerous enzymes, particular those involved in respiration; thus, their deficiency can lead to disturbances in central nervous system and other organ function. However, excessive tissue accumulation of redox-active transition metals can be cytotoxic, in particular because perturbations in metal homeostasis result in an array of cellular disturbances characterized by oxidative stress and increased free radical production. Oxidative stress, defined as the imbalance
Opposing oxidant damage is an array of antioxidant defenses that, in mammalian cells, include both enzymatic and nonenzymatic entities. Cytosolic copper-zinc superoxide dismutase (CuZnSOD) and mitochondrial manganese superoxide dismutase (MnSOD), which convert superoxide to 0, and H,O,, are important in enzymatic defences. H202 is removed by catalase and peroxidases, which have ubiquitous tissue distribution. The scope of this review is to evaluate recently published work that implicates redox-active transition-metal ions in oxidative stress contributing to neurodegeneration. The review will &icus not anly on roles of metalloenzymes implicated in oxidative stress and the a&.orp of adventitious ‘free’ trace metal ions, but also on metal-ion transport and storage
Redox
proteins closely tied to iron and copper homeostasis. Also, proteins not normally functioning as metal-binding proteins may sometimes act as neuroprotectants by sequestering the metal ions in redox inactive forms or as neurotoxicants by binding metals in a manner which retains redox activity
Antioxidant enzymes and proteins transition-metal homeostasis
involved
in
The development of transgenic mouse ‘knockout’ and overexpression models has permitted a range of studies to critically evaluate the extent to which selected biological processes affect cell viability. For example, if one or the other of the SOD enzymes serve a crucial antioxidant function, then knockout animals may exhibit increased oxidative stress parameters. This oxidative stress may be global or may be localized to the cellular compartment normally protected by the specific SOD enzyme. In support of this notion, MnSOD knockout mice, suffering a 50% drop in mitochondrial SOD activity but no reduction of CuZnSOD or glutathione peroxidase activity, were found to exhibit increased oxidative damage to mitochondria, as shown by increased mitochondrial protein carbonyls and 8hydroxydeoxyguanosine in mitochondrial DNA [Z’]. In contrast, no damage to cytosolic proteins or to nuclear DNA was observed. Analysis of homozygote knockouts showed mitochondrial degeneration that could only be followed for the two weeks that these mice lived [3’]. These results suggest that decreases in MnSOD activity in VZUO can explain increased oxidative damage in mitochondria and alterations in essential mitochondrial function. In other studies, overexpression of human CuZnSOD in mice, resulting in a tenfold higher level in both myocytes and endothelial cells, was able to quench a burst of superoxide (in electron paramagnetic resonance detection) and reduce functional damage following 30 minutes global ischemia [4]. These results suggest that superoxide is an important factor in protecting against postischemic injury and it is therefore surprising that CuZnSOD knockout mice show little if any neurodegenerative phenotype [S”]. Nonetheless, it is apparent that decreases in CuZnSOD activity can lead to a perturbation of cellular antioxidant defense mechanisms to promote a pro-oxidant condition. So, while absences of CuZnSOD have little effect, enzyme inactivation by metalcatalyzed oxidation promotes oxidative damage [6]. These surprising differences, while seemingly paradoxical, may be particularly relevant to human diseases, as discussed later. Ceruloplasmin (CP), an important copper storage protein, is one of the key proteins that responds to oxidative stress. CP is considered the major Fe(II)-oxidizing enzyme in the CNS, and an inherited metabolic disorder called aceruloplasminemia is associated with an impairment in iron homeostasis and consequent neurodegeneration [7]. Interestingly, while CP is increased in brain tissue and cerebrospinal fluid in AD, PD and Huntington’s disease (I-ID) patients [8], neuronal levels of CP remain unchanged [9]. Therefore, while increased CP may indicate a compensatory response to increased oxidative
metals
and neurodegenerative
disease
Sayre, Perry and Smith 221
stress in AD, its failure to do so in neurons may play an important role in metal-catalyzed damage [9]. In fact, studies directed at clarifying the relationship between oxidative stress and tissue metal-ion levels indicate that both the ratio of copper to zinc and the levels of CP are significantly higher with increasing age, and higher yet in cases with neurodegeneration [lo]. Since the copper : zinc ratio is significantly correlated with systemic oxidative stress, (i.e. lipid peroxidation), these findings suggest that increased oxidarive stress burden in aging and neurodegeneration may reflect, in large part, copper-mediated ROS production. In this case, redox-inert zinc may serve as an antioxidant by preventing binding of pro-oxidant copper at tissue sites. A novel glycolipid-anchored membrane-bound form of CP expressed by astrocytes in the mammalian CNS was recently identified [ll’], and it will be of interest to determine whether this form has any role in the neurodegenerative process. The escalating interest in prion diseases, (e.g. Creutzfeldt-Jakob disease), apparently caused by infection with an altered prion protein conformation that is transferred to endogenous protein, begs the question as to the normal role of this cell-surface glycoprotein in healthy individuals. In this regard, several lines of evidence indicate that the prion protein binds Cu(I1) and thus, as with CP, may serve a cytoprotective role [12”,13]. One possible scenario, consistent with the finding in cell cultures that copper stimulates endocytosis of prion protein from the cell surface, is that prion protein controls copper metabolism by serving as a recycling receptor for uptake of extracellular copper [ 14”].
CuZnSOD mutations lateral sclerosis
and familial
amyotrophic
A crucial breakthrough in our understanding of ALS comes from the finding that many of the familial cases (FALS) are associated with one or another mutation in the CuZnSOD gene. The protein products of these mutations retain nearly identical SOD activity, but take on altered properties linked to oxidative stress, possibly involving a gain-of-function peroxidase activity [ 151. In this regard, transgenic mice overproducing a human FALS CuZnSOD mutant display increases in protein carbonyls suggestive of increased hydroxyl radical production or lipoxidation-derived radicals [16*]. Also, using in viva microdialysis, increased hydroxyl radical production in the striatum, as determined by conversion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid, was seen for mice overexpressing mutant CuZnSOD relative to mice overexpressing the wild type human enzyme [17’]. The hypothesis that mutant SOD-induced neurodegeneration is associated with disturbances in neuronal free-radical homeostasis is further supported by observations made on several neuronal cell cultures expressing the mutant SOD [18’]; however, the mechanism underlying the link between the SOD mutations and oxidative stress indicators appears not to be simply increased production of hydroxyl radicals. since no increases in HO adducts are seen in vitro for the Gly93+Ala and Ala4+Val mutants relative to wild type enzyme [ 191.
222
Bio-inorganic
chemistry
Recent studies have shown that the mutant and wild type SODS differ neither in the rates of superoxide dismutation nor in another enzyme diagnostic, namely H20z-mediated inactivation [20’,21]. Structural analysis of the mutant enzymes revealed in some cases, alterations such as subunit asymmetry that suggest aberrant copper-mediated redox chemistry stemming from less tight folding and thus a more open ‘active site’ [22’,23]. Thus, the gain-of-function activity may reflect a ‘rechanneling’ of the enzyme to oxidize biomolecules that normally would never gain access to the: SOD oxidative half-reaction. Alternatively, the mutant SOD may possess weakened affinities for zinc or copper leading to a fraction of enzyme with abnormal activity [ 191 or oxidative reactions associated with leakage of copper [ZO’]. For the predominant, sporadic form of ALS, an imbalance in trace metal ions, possibly tied to increased oxidative stress, has been considered for some time. Recent studies provide evidence for decreases in copper in cerebrospinal fluid and serum, and increases in manganese in serum relative to age-matched controls [24].
Iron in neurodegenerative
disease
Free iron, more than any other transition metal, has been implicated in undergoing redox transitions in viva with the consequential generation of oxygen free radicals, which can, in turn, induce tissue oxidative stress. Abnormally high levels of iron and oxidative stress have been demonstrated in a number of neurodegenerative disorders including AD [25”] and those characterized by nigral degeneration such as PD, multiple system atrophy and progressive supranuclear palsy. Since oxidative stress is usually associated with increased free iron, experimental findings of increased total iron do not necessarily implicate increased oxidative stress if there are concomitant increases in proteins that store iron in redox-inert forms. For example, ferritin (Ft; which may be upregulated in PD and AD) contains a core of insoluble, unreactive ferrihydrate. However, the entry and release of iron from Ft occurs via its more coordinatively labile ferrous state, active in Fenton generation of hydroxyl radicals. Microglia (macrophage-like cells in the central nervous system) are the major sites of Ft bound iron and are thought to be partly responsible for oxidative damage in PD and other neurodegenerative disorders. Microglia stimulated in vivo with phorbol ester show increased lipid peroxidation resulting from a superoxide-dependent release of iron from Ft [26]. Besides superoxide, ferritin iron can be releasedby 6-hydroxydopamine, a neurotoxin implicated in PD, and other easily oxidized catechols [27]. These studies suggest that Ft iron releasecontributes to free-radical-induced cell damage in Gvo via Fenton production of hydroxyl radicals. In addition, the interplay between oxidative stressand control of iron metabolism in the brain is exemplified by the finding of abnormal iron deposition associated with lipid peroxidation in a transgenie mouse model (expressing interleukin-6 in astrocytes) of a blood-brain barrier defect associatedwith progressive neurodegeneration [ZS].
In recent years, it has become evident that the regulation and management of iron at the cellular level, although primarily by the transferrin (Tf) receptor and Ft, is also under the control of the lactotransferrin receptor, melanotransferrin, CP and divalent cation transporter 1. Thus, disruption in the expression of these latter proteins in the brain also probably contributes to altered brain-iron metabolism of age-related neurodegenerative disorders such asPD, AD, HD and ALS [29’]. Overall regulation of cellular iron metabolism, involves the action of two iron regulatory proteins, IRP-1 and IRP-2. IRP-1, but not IRP-2, is rapidly activated by extracellular H,O,, establishing a regulatory connection between the control of iron metabolism and responseto oxidative stress. This activation has recently been recapitulated in aha, and shown not to occur directly, but to require the presence of a cellular membrane-associated component sensitive to temperature and alkaline phosphatase [30”]. Further studies in this area should lead to a more clear understanding of the causative link between iron-induced oxidative stress and neuronal death. Interestingly, IRPs show significant alterations in AD patients [31], paralleling alterations in redox-active iron [25”].
Iron-mediated oxidative stress substantia nigra in Parkinson’s
in the disease
Despite the recent identification of a mutation in the a-synuclein gene in certain casesof familial Parkinsonism, which may ultimately lead to an understanding of the biochemical mechanisms of selective dopaminergic cell death in these cases,the etiology of the diseaseremains undefined. Nonetheless, several biochemical abnormalities in PD brain tissue have been identified, including a mitochondrial complex I deficiency, oxidative stress and excessiron. Iron accumulates in astrocytes in the substantia nigra of old rats [32,33] and at the sametime there is an increase in the Fe(II1) : Fe(I1) ratio and a decrease in reduced glutathione [34]. One interpretation is that mitochondrial sequestration of redox-active iron in aging nigral astroglia may be one factor predisposing the senescent nervous system to Parkinsonism and other neurodegenerative disorders. In fact, a persistent condition of oxidative stressassociatedwith greatly perturbed intracellular redox equilibria is widely recognized as a pathogenetic factor underlying neurodegeneration. Moreover, there is circumstantial evidence that the intracellular redox imbalance results in aberrant oxidation of dopamine to 6-hydroxydopamine, which in turn can undergo autoxidation to the corresponding quinone concomitant with generation of superoxide. This reaction cascade, either by itself, or as amplified by redox cycling of this quinone leading to further generation of ROS at the expense of cellular reductants, can serve to explain the ultimate demise of these neurons. Studies to clarify the mechanism of dopamine oxidation in vitro have demonstrated conversion to 6-hydroxydopamine in the presence of Fe(H) and either H,OZ or alkyl peroxides [35].
Redox
The role of manganese
in Parkinson’s
disease
Chronic exposure to manganese results in extrapyramidal syndromes resembling PD, and manganese has therefore been labeled as an environmental toxic factor that induces brain dysfunction. One suggestion is that manganese acts as a dopaminergic neurotoxin, in the same manner as iron, by mediating the generation of ROS and the subsequent nonenzymatic autoxidation of dopamine to the neurotoxin 6-hydroxydopamine. There is no convincing in viva evidence for a pro-oxidant role of manganese in the brain, however. Also, the clinical picture of manganese-induced Parkinsonism is by no means clear, because there is conflicting evidence regarding whether it is selectively toxic to dopaminergic neurons. Additionally, recent findings suggest that manganese actually may act as an antioxidant rather than pro-oxidant [36]. In this study, Mn(I1) was found to protect, dose-dependently, against the toxicity of Fe(I1) administered intranigrally to rats. This protection could result from the fact that Mn(II), itself inactive in Fenton chemistry, competes with Fe(I1) in oxidative cascades. It thus appears that the Parkinsonian-like syndrome induced by chronic manganese poisoning may have little connection to nigrostriatal damage occurring in idiopathic PD.
Redox-active Alzheimer’s
transition disease
metals
in
AD is characterized pathologically by the presence of neurofibrillary tangles (NFT), senile plaques (SP), neuropil threads, amyloid-P (Afl) deposition, and a selective loss of neurons. Much excitement in recent years has come from the discovery of a multiplicity of mutations in the genes encoding the P-protein precursor (PPP) and/or the presenilins, which account for the bulk of the familial cases of AD on the basis of overproduction of PPP and/or altered PPP proteolytic processing, both leading to increased AP. Transgenic mice overproducing the human mutations have been shown to develop SP and some neurotoxicity, but the mechanism of this neurotoxicity may be unrelated to neuronal loss that occurs in AD, and no complete animal model for even familial AD exists. Moreover, the predominance of AD is sporadic. Of the various hypotheses that have been suggested for the etiology of sporadic AD, the one receiving most recent attention is a role for oxidative stress. Several studies have indicated imbalances of trace elements, including aluminiurn, silicon, lead, mercury, zinc, copper and iron. A disruption of homeostasis of copper and iron is particularly significant in light of substantial, recent evidence for increases in oxidative stress parameters such as lipid peroxidation, as well as increases in markers of oxidative damage to both the protein constituents of the pathological hallmark structures of AD (NFT and SP) [37,38*,39,40*] and nucleic acids [41”]. Using microparticle-induced X-ray ly found that Zn(II), Fe(II1) and elevated in AD neuropil and that cantly further concentrated within
emission, it was recentCu(I1) are significantly these metals are signifithe core and periphery
metals
and neurodegenerative
disease
Sayre,
Perry and Smith
223
of senile plaques [42’]. These results extend earlier studies reporting increased levels of iron, Tf and Ft in AD. Using an in sitti iron detection method, we found a marked association of redox-active iron with both NFT and SP in AD [ZS”]. The association of iron with NFT may be, in part, related to iron binding to their primary protein constituent, z [43]. At the same time, as discussed earlier, whereas IRP-1 was found to be present in similar levels in both AD and control brain tissue, IRP-2 co-localized with redox-active iron in NFT, SP neurites, and neuropil threads [31]. These results suggest that alterations in IRP-2 may be directly linked to impaired iron homeostasis in AD. In recent histochemical studies, we found that redox activity of the lesions in AD can be detected directly, can be inhibited by prior exposure of tissue sections to copper- and iron-selective chelators, and can be reinstated following reexposure of the chelator-treated sections to either copper or iron salts (LM Sayre and co-workers, unpublished data). Our studies indicating the presence of redox-active iron and probably also copper in AD pathology suggest that these metal accumulations are major producers of the ROS responsible not only for the numerous oxidative stress markers that appear on NFT and SP, but also for the more global oxidative stress parameters observed in AD. Other studies of oxidative stress in AD have focused on the inducible mitochondrial MnSOD and the constitutive cytoplasmic CuZnSOD enzymes. The CuZnSOD gene is associated with AD neuropathology, and levels of both MnSOD mRNA and CuZnSOD were found to be increased in AD, whereas the total antioxidant status was decreased [44]. However, since SOD enzymes are key components of the cellular antioxidant armementarium, any pro-oxidant mechanism linked to SOD must derive from the balance in the local concentrations of superoxide and H,O,, which together can produce the hydroxyl radical by the Haber-Weiss process.
The role of metal ions in the aggregation Ap and @PP/Aplinked reactive oxygen species production
of
Evidence for an imbalance of trace-metal homeostasis in AD have led, over the years, to efforts to identify possible effects of metal ions on the aggregation of A& For example, it was found that aluminium, iron and zinc but not calcium, cobalt, manganese, copper, magnesium, sodium or potassium accelerated aggregation of AP [45]. More recent studies, however, suggest that the aggregatory effect of metals depends critically on the pH. It was found that Cu(I1) induced aggregation of A@ l-40) when the pH was lowered from 7.4 to 6.8, a phenomenon that was not common to other metals tested [46’]. ,4 mildly acidic environment, together with increased Zn(I1) and Cu(II), are common features of inflammation associated with increased oxidative damage stemming from microglial-derived peroxynitrite. The association of Cu(II), Zn(I1) and Fe(I1) with A@ seen in a& could explain the enrichment of these metals with SP in AD.
224
Bio-inorganic
chemistry
It is interesting to note in these studies on Afi aggregation that the effect of the transition metal is not purported to involve a redox role. This contrasts with other results suggesting a synergistic action of AD and copper or iron in mediating ROS production [47]. Also, Cu(II) binds to PPP and appears to be reduced to Cu(1) concomitant with production of a disulfide linkage [48). Subsequent exposure to H,O, results in reoxidation of Cu(1) and concomitant sitespecific cleavage of J3PP Redox chemistry associated with AD- or PPP-bound metals could contribute to a perturbation of free-radical homeostasis.
Over the past year or so, there has been an increasing awareness of the seminal role that redox-active transition metals play in a variety of neurodegenerative diseases. The stage is now set to critically examine the importance of these basic research findings as they are translated into therapeutic modalities such as antioxidants and chelating agents that are being used clinically. The next two to three years will be truly fascinating to watch unravel.
Papers of particular have been highlighted l
**of 1.
laboratories is supported the Alzheimer’s Association
and recommended interest, as:
published
within
reading the annual
period
of review,
of special interest outstanding interest Smith MA, Sayre LM, Perry G: Primary involvement of oxidative damage and redox imbalance in Alzheimer and other neurodegenerative diseases. In Redox Regulation of Cell Signaling. Edited by Packer L, Yodoi J. New York: Marcel Dekker, Inc; 1988:115-126.
Melov S, Schneider Crapo JD, Wallace lacking mitochondrial Genef 1998,18:159-l This paper describes a mutase knockout mice tion. Mice die within two
JA, Day BJ, Hinerfeld D, Coskun P, Mirra SS, DC: A novel neurological phenotype in mice manganese superoxide dismutase. Nat 63. morphological study of manganese superoxide disshowing mitochondrial welling and axonal vacuolaweeks of birth.
Wang P, Chen H, Qin H, Sankarapandi S, Becher MW, Wong PC, Zweier JL: Overexpression of human copper, zinc-superoxide dismutase (SOD1 1 prevents postischemic injury. Proc Nat/ Acad SC; USA 1998, 95:4556-4560.
5. ..
Bruijn LI, Houseweari MK, Kato S, Anderson KL, Anderson SD, Ohama E, Reaume AG, Scott RW, Cleveland DW: Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type 5001. Science 1998, 281 :1851-l 854. In addition to showing, as many previous studies have, that mutant Cu-Zn superoxide dismutase is associated with neurodegenerative damage, the knockout of this enzyme is shown to have no obvious neurodegenerative phenotype. 6.
9.
Castellani RJ, Smith MA, Nunomura A, Harris PLR, Perry G: Is increased redox-active iron in Alzheimer disease a failure of the copperbinding protein ceruloplasmin? Free Radical Biol A&d 1999, in press,
10.
Meuetti A, Pierdomenico Cuccurullo F, lmbastaro Fellin R: Copper/zinc aging and aging-related Med 1998, 25:676-681,
SD, Costantini T, Riario-Sforza ratio and systemic degenerative
AJ,
F, Roman0 F, De Cesare D, G, Di Giacomo F, Zuliani G, oxidant load: effect of diseases. Free Radical Biol
Pate1 BN, David S: A novel glycosylphosphatidylinositol-anchored from of ceruloplasmin is expressed by mammalian astrocytes. J Biol Chem 1997, 272:20 185-20190. A novel membrane-bound form of ceruloplasmin (CP) expressed by astrocytes in the mammalian CNS is reported. In the liver, CP is the major Fe(ll)-oxidizing enzyme, and this could be the same role for the CP in the CNS, as appears to be the case in aceruloplasminemia. Lack of this form could contribute to neuronal degeneration in Parkinson’s disease and Alzheimer’s disease. 12. ..
Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Truck T, von Bohlen A, Schulz-Schaeffer W et a/.: The cellular prion protein binds copper in viva. Nature 1997,390:684-687. The normal cellular form of prion protein binds Cu(ll) nearly as strongly does serum albumin. Thus, binding of Cu(ll) to prion protein may indicate cytoprotective role of this protein. Brown survival 1998,
DR, Schmidt B, Kretzschmar of prion protein knockout 70:1686-l 693.
as a
HA: Effects of copper on neurons and glia. J Neurochem
14.
Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardon A: Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 1998, 273:2851 O-2851 5. Manganese superoxide dismutase (MnSOD) knockout mice, exhibiting a 50% drop in mitochondrial activity of MnSOD but not CuZnSOD or glutathione peroxidase, witness an increased oxidative damage to mitochondria as shown by increased mitochondrial protein carbonyls and 8-hydroxydeoxyguanosine in mitochondrial DNA. No damage to cytosolic proteins or to nuclear DNA was observed.
4.
an inherited homeostasis.
Loeffler DA, LeWitl PA, Juneau PL, Sima AA, Nguyen HU, DeMaggio Bridunan CM, Brewer GJ, Dick RD, Troyer MD, Kanaley L: Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders Brain Res 1996, 738:265-274.
by grants from the Kational and the American Health
2. .
3. .
of iron
8.
13.
Acknowledgements
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Conclusions
Work in the authors’ Institutes of Health, Assistance Foundation.
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Andrus PK, Fleck TJ, Gurney ME, Hall ED: Protein oxidative damage in a transgenic mouse model of familial amytrophic lateral sclerosis. I Neurochem 1998, 7112041-2048. In familial amylotrophic lateral sclerosis mice overexpressing the GlyOS-tAla mutation, there is increased protein carbonyl levels signifying increased hydroxyl radical production and/or lipid peroxidation.
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Bogdanov MB, Ramos LE, Xu Z, Beal MF: Elevated ‘hydroxyl radical’ generation in viva in an animal model of amyotrophic lateral sclerosis. J Neurochem 1998, 71 :1321-1324. Using in viva microdialysis, there is an increase in hydroxyl radicals, as determined by conversion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid (3,4-DHBA), in the striatum for mice overexpressing mutated Cu,Zn-superoxide dismutase but not for overexpression of the wild type enzyme. 3-Nitropropionic acid increases baseline production of 3,4-DHBA in controls but, whereas the increase was greater in the amyotrophic lateral sclerotic mice, the increase was less in mice overexpressing the wild type enzyme. 18. .
Ghadge GD, Lee JP, Bmdokas VP, Jordan J, Ma L, Miller RJ, Roos RP: Mutant superoxide dismutase-1 -linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection. J Neurosci 1998, 17:8756-8766. Expression of Ala4-tVal and Vall48+Gly Cu, Zn-superoxide dismutase mutants in differentiated neuronal PC12 cells, superior cervical ganglion neurons, and hippocampal pyramidal neurons had higher rates of superoxide production and resulted in cell death exhibiting many features of apoptosis. Cell death could be prevented by copper chelators, Bcl-2, glutathione, vitamin E, and inhibitors of caspases. 19.
20. .
Singh RJ, Karoui H, Gunther MR, Beckman JS, Mason RP, Kaiyanaraman Reexamination of the mechanism of hydroxyl radical adducts formed from the reaction between familial amyotrophic lateral sderosis-associated Cu,Zn superoxide dismutase mutants and H,O,. Proc Nat/ Acad Sci USA 1998,95:6675-6680.
B:
Goto JJ, Gralla EB, Valentine JS, Cabelli DE: Reactions of hydrogen peroxide with familial amyotrophic lateral sclerosis mutant human copper-zinc superoxide dismutases studies by pulse radiolysis. J Biol Chem 1998, 273:30 104-30 109. The wild type and Gly93-+Ala Cu-Zn-superoxide dismutase (SOD) mutant are compared. Both have high SOD activity as do the Cu-Cu forms. Both
Redox
metals
35
and
neurodegenerative
k%~?ei~d&
dk%d
disease
bt, &pTih%ITU~,
Sayre,
Perry
i%WdCd~,
Red
71~~~~~,~iiur~~tt7~u#n,~tyLi~~inr quinone by reaction of fatty acid hydroperoxides possible contributory mechanism for neuronal Parkinson’s disease. J Med Chem 1997,40:221 21.
Liochev SI, Chen LL, Hallewell RA, Fridovich amyotrophic lateral sclerosis-associated El OOG, G93A, and GS3R do not influence of copperand zinc-containing superoxide Arch Biochem Biophys 1998, 352:237-239.
I: The familial amino acid substitutions the rate of inactivation dismutase by H,O,.
Smith MA, Sayre LM, products froc Nat/
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Hart PJ, Liu H, Pellegrini M, Nerscssian AM, Gralla EB, Valentine Eisenberg D: Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis. Protein Sci 1998, 7:545-555.
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Smith MA, Harris PLR, Sayre LM, Perry G: Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Nat/ Acad Sci USA 1997, 94:9866-9868. Neurofibrillary tangles and senile plaques In Alzheimer’s disease accumulate iron and possibly other redox-active transition metals, as indicated by catalysis of H,O1-dependent oxidation of 3,3’-dlaminobenzidine (DAB) or appli‘cation of P&l’s’ method followed by DAB enhancement. Both Fe(ll) ‘and Fe(lll) were detected.
l
Yoshlda T, Tanaka M, Sotomatsu microglia cause iron-dependent of ferritin. NeuroReport 1998,
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K: Activated in the presence
KL, Maywald M, Schmittel M, Rlederer P, Gerlach M: In vitro of ferritin iron release and neurotoxicity. I Neurochem 70:2492-2499.
Smith MA, Harris PLR, Sayre LM, Beckman JS, peroxynitrite-mediated damage in Alzheimer’s 1997,17:2653-2657. Neurotlbnllary tangle-contalnmg neurons as well as pocampal neurons in Alzheimer disease, but not in cation by peroxymtrite in the form of protein tyrosine
C&an ZM, Wang 0: Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders. Brain Res Rev 1998, 27:257-267. . Abnormally high levels ot Iron and oxldatlve stress have been demonstrated in a number of neurodegenerative disorders, but there is no general agreement as to the causative link between iron-induced oxidative stress and neuronal death. Regulation/management of iron at the cellular level is primarily by the transferrln receptor and ferntin, but recent focus on the roles of the lactotransferrin receptor, melanotransferrin, ceruloplasmin, and divalent cation transporter, suggest that disruption in the expresston of these proteins in the brain is probably one of the important causes of altered brain iron metabolism of age-related neurodegenerative disorders such as Parkinson’s, Alzheimer’s and Huntington’s diseases and amyotrophic lateral sclerosis. Pantopoulos K, Hentze MW: Activation of iron regulatory protein-l by oxidative stress in vitro. Proc Nat/ Acad Sci USA 1998, 95:10559-10563. Iron regulatory protein-l (IRP-I), but not IRP-2, is rapidly activated by extracellular H,O, to bind iron-responsive elements on mRNA. Characterization of activation in ntro revealed that it does not occur directly, but requires the presence of a cellular membrane-associated component sensitive to temperature and alkaline phosphatase. SL, Connor protein
32.
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end
Perry G: Widespread disease. J Neurosci apparently controls, nitration.
normal hipexhibit modifi-
Smith MA. Savre LM. Anderson VE. Harris PLR. Beal MF. Kowall N. Perry G: Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with dinitrophenylhydrazine. J Histochem Cytochem 1998,46:731-735.
Sayre LM, Zelasko DA, Harris PLR, Perry G, Salomon RG, Smith MA: 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 1997, 68:2092-2097. Antibodles selective for the stable, advanced 2-pentylpyrrole modification of protein lysines by 4-hydroxynonenal stain neurofibrillatory tangles (NFT-containing neurons, extracellular NFT, as well as apparently normal neurons in Alzheimer disease cases but not in controls. 41. .
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l
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K,
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42. .
29. .
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a
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with dopamine: degeneration in I-221 6.
37.
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Corson LB, Strain JJ, Culotta VC, Cleveland DW: Chaperonefaciliated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants. froc Nat/ Acad Sci USA 1998, 956361-6366. An analysis of a broad range of Cu,Zn-superoxide dismutase (SOD) mutants in Saccharomyces cerevisiae was carried out: all appear to bind copper and scavenge superoxide in viva. These results support a mechanism of SOD1 mutant-mediated disease arising from aberrant copper-mediated chemistry catalyzed by less tightly folded (and less constrained) mutant enzymes. All mutants acquire copper m viva via action of the copper chaperone for SOD1
T, Kakami A, alterations in Sci 1997, 147:171-l
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JS,
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