Monomeric Cu,Zn-superoxide Dismutase Is a Common Misfolding Intermediate in the Oxidation Models of Sporadic and Familial Amyotrophic Lateral Sclerosis (2004)

Proteinacious intracellular aggregates in motor neurons are a key feature of both sporadic and familial amyotrophic lateral sclerosis (ALS). These inclusion bodies are often immunoreactive for Cu,Zn-superoxide dismutase (SOD1) and are implicated in the pathology of ALS. On the basis of this and a similar clinical presentation of symptoms in the familial (fALS) and sporadic forms of ALS, we sought to investigate the possibility that there exists a common disease-related aggregation pathway for fALS-associated mutant SODs and wild type SOD1. We have previously shown that oxidation of fALS-associated mutant SODs produces aggregates that have the same morphological, structural, and tinctorial features as those found in SOD1 inclusion bodies in ALS. Here, we show that oxidative damage of wild type SOD at physiological concentrations (∼40 μm) results in destabilization and aggregation in vitro. Oxidation of either mutant or wild type SOD1 causes the enzyme to dissociate to monomers prior to aggregation. Only small changes in secondary and tertiary structure are associated with monomer formation. These results indicate a common aggregation prone monomeric intermediate for wild type and fALS-associated mutant SODs and provides a link between sporadic and familial ALS. Proteinacious intracellular aggregates in motor neurons are a key feature of both sporadic and familial amyotrophic lateral sclerosis (ALS). These inclusion bodies are often immunoreactive for Cu,Zn-superoxide dismutase (SOD1) and are implicated in the pathology of ALS. On the basis of this and a similar clinical presentation of symptoms in the familial (fALS) and sporadic forms of ALS, we sought to investigate the possibility that there exists a common disease-related aggregation pathway for fALS-associated mutant SODs and wild type SOD1. We have previously shown that oxidation of fALS-associated mutant SODs produces aggregates that have the same morphological, structural, and tinctorial features as those found in SOD1 inclusion bodies in ALS. Here, we show that oxidative damage of wild type SOD at physiological concentrations (∼40 μm) results in destabilization and aggregation in vitro. Oxidation of either mutant or wild type SOD1 causes the enzyme to dissociate to monomers prior to aggregation. Only small changes in secondary and tertiary structure are associated with monomer formation. These results indicate a common aggregation prone monomeric intermediate for wild type and fALS-associated mutant SODs and provides a link between sporadic and familial ALS. ALS 1The abbreviations used are: ALS, amyotrophic lateral sclerosis; fALS, familial ALS; sALS, sporadic ALS; SOD1, Cu,Zn-superoxide dismutase; MCO, metal-catalyzed oxidation; ANS, 8-anilino-1-napthalene-sulfonic acid; DLS, dynamic light scattering; DSC, differential scanning calorimetry; CD, circular dichroism; MS, mass spectrometry. 1The abbreviations used are: ALS, amyotrophic lateral sclerosis; fALS, familial ALS; sALS, sporadic ALS; SOD1, Cu,Zn-superoxide dismutase; MCO, metal-catalyzed oxidation; ANS, 8-anilino-1-napthalene-sulfonic acid; DLS, dynamic light scattering; DSC, differential scanning calorimetry; CD, circular dichroism; MS, mass spectrometry. is a fatal neurodegenerative disease that leads to the selective loss of motor neurons. Although ALS is predominately a sporadic disease, ∼10% of cases are inherited in an autosomal dominant manner and a subset of these fALS cases are caused by mutations in the SOD1 gene (1Majoor-Krakauer D. Willems P.J. Hofman A. Clin. Genet. 2003; 63: 83-101Crossref PubMed Scopus (130) Google Scholar). The gene product of SOD1, cytoplasmic Cu,Zn-superoxide dismutase (SOD1), is a ubiquitously expressed enzyme that catalyzes the disproportionation reaction of superoxide radicals (1Majoor-Krakauer D. Willems P.J. Hofman A. Clin. Genet. 2003; 63: 83-101Crossref PubMed Scopus (130) Google Scholar). There are several lines of evidence that SOD1 mutations result in a gain, rather than loss of function that causes ALS. For instance, some fALS-associated mutant SOD1s retain full enzymatic activity (2Borchelt D.R. Lee M.K. Slunt H.S. Guarnieri M. Xu Z.S. Wong P.C. Brown Jr., R.H. Price D.L. Sisodia S.S. Cleveland D.W. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8292-8296Crossref PubMed Scopus (524) Google Scholar). In addition, SOD1 knock-out mice lack ALS symptoms, whereas transgenic mice expressing the fALS-associated mutant G93A SOD1 develop ALS-like symptoms despite expression of endogenous mouse SOD1 (3Bruijn L.I. Houseweart M.K. Kato S. Anderson K.L. Anderson S.D. Ohama E. Reaume A.G. Scott R.W. Cleveland D.W. Science. 1998; 281: 1851-1854Crossref PubMed Scopus (985) Google Scholar). Lastly, overexpression of human wild type SOD1 fails to alleviate symptoms in this transgenic mouse model for ALS (3Bruijn L.I. Houseweart M.K. Kato S. Anderson K.L. Anderson S.D. Ohama E. Reaume A.G. Scott R.W. Cleveland D.W. Science. 1998; 281: 1851-1854Crossref PubMed Scopus (985) Google Scholar). One hypothesis of the gain of function of SOD1 is that misfolding of the mutant alters the catalytic mechanism to allow production of oxidants such as peroxynitrite (4Estevez A.G. Crow J.P. Sampson J.B. Reiter C. Zhuang Y. Richardson G.J. Tarpey M.M. Barbeito L. Beckman J.S. Science. 1999; 286: 2498-2500Crossref PubMed Scopus (509) Google Scholar) and possibly hydrogen peroxide (5Yim M.B. Kang J.H. Yim H.S. Kwak H.S. Chock P.B. Stadtman E.R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5709-5714Crossref PubMed Scopus (428) Google Scholar). These reactive nitrogen and oxygen species cause toxicity by accumulated damage to proteins, nucleic acids, and lipids. Another major hypothesis is toxicity caused by intracellular aggregation of SOD1. SOD1 inclusion bodies, which also react with anti-ubiquitin antibodies, are a common pathological finding in motor neurons and neighboring astrocytes of ALS patients (6Watanabe M. Dykes-Hoberg M. Culotta V.C. Price D.L. Wong P.C. Rothstein J.D. Neurobiol. Dis. 2001; 8: 933-941Crossref PubMed Scopus (344) Google Scholar). These two hypotheses, however, are not mutually exclusive when considering that oxidative modification of proteins may contribute to aggregation and protease resistance. Protein aggregates are a common pathological feature of many neurological disorders (7Caughey B. Lansbury P.T. Annu. Rev. Neurosci. 2003; 26: 267-298Crossref PubMed Scopus (1437) Google Scholar), including Huntington's, Alzheimer's, and Parkinson's diseases. In each case, misfolding and aggregation appears to be linked to cytotoxicity (7Caughey B. Lansbury P.T. Annu. Rev. Neurosci. 2003; 26: 267-298Crossref PubMed Scopus (1437) Google Scholar). Similarly, the aggregation propensity of mutant SOD1s may be the mechanism by which over 100 disparate mutations cause a common ALS phenotype. SOD1 aggregates may be inherently toxic or cause motor neuron toxicity by sequestering chaperones and blocking proper functioning of the proteasome (8Bence N.F. Sampat R.M. Kopito R.R. Science. 2001; 292: 1552-1555Crossref PubMed Scopus (1803) Google Scholar). Indeed, overexpression of either the chaperone Hsp70 (9Bruening W. Roy J. Giasson B. Figlewicz D.A. Mushynski W.E. Durham H.D. J. Neurochem. 1999; 72: 693-699Crossref PubMed Scopus (222) Google Scholar) or the ubiquitin E3 ligase Dorfin (10Niwa J. Ishigaki S. Hishikawa N. Yamamoto M. Doyu M. Murata S. Tanaka K. Taniguchi N. Sobue G. J. Biol. Chem. 2002; 277: 36793-36798Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar) preserves the viability of cells expressing fALS mutant SOD1s by decreasing the number of intracellular SOD1 aggregates. Understanding the details of the biophysical pathway by which SOD1 aggregation occurs might then yield avenues for novel therapeutics for ALS. To carry out such an investigation, we previously developed a physiologically relevant cell-free model of SOD1 aggregation (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). As a natural free radical scavenger and metalloprotein, SOD1 in motor neurons is exposed to greater oxidative stress than other proteins. Based on this occupational hazard, as well as the long half-life (12Borchelt D.R. Wong P.C. Becher M.W. Pardo C.A. Lee M.K. Xu Z.S. Thinakaran G. Jenkins N.A. Copeland N.G. Sisodia S.S. Cleveland D.W. Price D.L. Hoffman P.N. Neurobiol. Dis. 1998; 5: 27-35Crossref PubMed Scopus (93) Google Scholar) and high concentration of SOD1 in motor neurons (13Pardo C.A. Xu Z. Borchelt D.R. Price D.L. Sisodia S.S. Cleveland D.W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 954-958Crossref PubMed Scopus (258) Google Scholar), we proposed that SOD1 is especially susceptible to oxidation-induced aggregation in motor neurons. Indeed, it has been shown that ALS patients display higher levels of oxidative stress than age-matched controls (14Ferrante R.J. Browne S.E. Shinobu L.A. Bowling A.C. Baik M.J. MacGarvey U. Kowall N.W. Brown Jr., R.H. Beal M.F. J. Neurochem. 1997; 69: 2064-2074Crossref PubMed Scopus (655) Google Scholar) and transgenic mouse models for fALS also show higher levels of oxidized SOD1 (15Andrus P.K. Fleck T.J. Gurney M.E. Hall E.D. J. Neurochem. 1998; 71: 2041-2048Crossref PubMed Scopus (234) Google Scholar). In our cell-free model, we used metal-catalyzed oxidation (MCO), a physiologically relevant process, to induce oxidative stress. MCO may represent the major cause of SOD1 aggregation in vivo, because it is the major source of hydroxyl radicals in vivo, it has been implicated as a major cause of protein modification in aging, and it marks proteins for degradation (16Stadtman E.R. Oliver C.N. J. Biol. Chem. 1991; 266: 2005-2008Abstract Full Text PDF PubMed Google Scholar). Our results showed that fALS-associated mutants of SOD1 were extremely prone to form visible aggregates upon oxidation compared with wild type protein (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). Examination of the morphology, structure, and tinctorial properties of these aggregates demonstrated their similarity to those found in intracellular inclusion bodies seen in ALS patients and in cell lines. ALS inclusion bodies are not stained with the amyloid dye Congo Red (17Okamoto K. Hirai S. Yamazaki T. Sun X.Y. Nakazato Y. Neurosci. Lett. 1991; PubMed Scopus Google Scholar) and are of a of aggregates and some T. S. K. R. T. M. S. Neurosci. Lett. 1998; PubMed Scopus Google S. K. E. Kato M. A. K. Ohama E. J. 1997; Google S. M. A. Ohama E. 1999; Google S. K. S. R. Cleveland D.W. J. A. M. Kato M. S. K. Ohama E. 2001; Google Scholar) as compared with seen in amyloid (7Caughey B. Lansbury P.T. Annu. Rev. Neurosci. 2003; 26: 267-298Crossref PubMed Scopus (1437) Google Scholar). Examination of SOD1 aggregates in our model by and dye demonstrated that properties with in aggregates. the in aggregates circular with aggregation seen in (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). In this we used the same model to the of the SOD1 aggregation and fALS have similar clinical and inclusion bodies are seen in both forms of the disease K. A. M. S. T. K. 2003; PubMed Scopus Google Scholar). inclusion bodies that are SOD1 immunoreactive are of fALS D.W. Rothstein J.D. Rev. Neurosci. 2001; PubMed Scopus Google Scholar), whereas inclusion bodies, which be SOD1 immunoreactive H.S. R. J. Sci. 1999; Full Text Full Text PDF PubMed Scopus Google S. N. T. T. Clin. 1996; Google N. A. M. S. Kato T. S. Z. T. A. T. K. Neurosci. Lett. 1994; PubMed Scopus Google Scholar), are found in motor neurons of patients D.W. Rothstein J.D. Rev. Neurosci. 2001; PubMed Scopus Google Scholar). We our model with demonstrated in (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar) to and the aggregation of wild type and mutant SOD1 to the and in the sporadic and familial forms of the We that SOD1, a to monomers prior to aggregation for both wild type and mutant proteins. is by changes in the secondary structure of SOD1. common intermediate a common pathway for the aggregation of mutant and wild type SOD1 and provides a link between sporadic and familial ALS. In of type SOD1 human and of the other were human SOD1s were as previously (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). MCO of SOD1, and in whereas were SOD1 in were at for were with a and were to of the were prior to to aggregates. and SOD1 were for with with at The to were with a Protein at MCO for either wild type SOD1 or mutant SOD1 were by the of were used for the by for each of the for each were and to a of and a of for at on a Beckman an cells were for prior to of at Beckman were to the The and of the were the the and scanning were a of oxidized and SOD1 were to mass of and SOD1s in were The protein used as a and were at scanning to at of oxidized and SOD1 were on an at in a cell were on a with to and a of μm) with at for The protein and with and in and then with to enzyme at for and by were a mass to a high The of the that not to the to the by were by and were and in a with SOD1 aggregation is inherently a To the physiological of our in aggregation we used concentrations of SOD1. N. K. Kato K. Clin. PubMed Scopus Google Scholar) found that the SOD1 of is of which to a concentration of on for and J. of The concentration of SOD1 is greater in than in N. K. Kato K. Clin. PubMed Scopus Google Scholar), to a concentration of SOD1 concentration in motor neurons may be higher (13Pardo C.A. Xu Z. Borchelt D.R. Price D.L. Sisodia S.S. Cleveland D.W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 954-958Crossref PubMed Scopus (258) Google Scholar). we used the concentration MCO of SOD1 at used to induce aggregation. The concentration of the aggregation reaction by light is shown in concentrations of SOD1, light both oxidized and were to that protein aggregates were SOD1 concentrations caused the of visible aggregates in oxidized not in at levels were to SOD1 however, the 100 oxidized SOD1 is than the SOD1 (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). The of light is to both the and number of there be either or aggregates in the of wild type than SOD1. These that the aggregation propensity of wild type SOD1 is than that of SOD1 or fALS-associated SOD1 is a selective of the of a protein and is to for K. PubMed Scopus Google Scholar). The to is shown in a in in the MCO over the in the of SOD1 and with concentration of SOD1, possibly because of to SOD1. These however, are small compared with the in upon SOD1 aggregates. The is a of the of protein and the in light the for the of both oxidized and SOD1. The of SOD1 two with and The higher is dominant and to the of the SOD1, whereas the is of SOD1 P.B. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). SOD1 at in a that is similar to that of the The of SOD1 and the of a high is visible at 100 the high is by a at which is the result of aggregation. there are some changes to the SOD1 structure upon at SOD1 a in the to which is of an in aggregation at a than that for SOD1. to the of SOD1 at is also the of this is to because of evidence of a at to SOD1 for the oxidized SOD1. as a these results indicate that metal-catalyzed oxidation of wild type SOD1 a species that is and aggregates at high concentrations SOD1 to prior to is in ubiquitously as a with E.D. Richardson J.S. Richardson J. Biol. PubMed Scopus Google Scholar). To investigate the of SOD1 we used and to the and species The then by We found that SOD1 has a of to a mass of or the mass of the not the of DLS, the results indicate that SOD1 is as oxidation for however, the results show the major species to be to a mass of or the monomer the of the of each are shown in are of of the for an in by an results were the fALS mutant SOD1 of for the of SOD1 monomers as an intermediate prior to aggregation. used to the of oxidized and SOD1. at of in the Beckman for oxidized and wild type SOD1 at are shown in The mass of SOD1 which is to the mass SOD1, however, has a mass of of the The for oxidized SOD1 also be by a with of for the mutant G93A SOD1 a mass of for the and for the oxidized G93A SOD1 the for oxidized G93A SOD1 be by a with SOD1 are for both wild type and G93A mutant SOD1 is small to by whereas both wild type and G93A mutant SOD1 as a of monomers and upon Based on the of the oxidized SOD1s and the concentrations in motor neurons a of the oxidized proteins be monomeric in to of SOD1 upon have that SOD1 and at monomeric upon structure is upon high protein higher than those at which oxidized SOD1 To the changes to SOD1 structure upon we to changes in secondary structure and to changes in tertiary structure and The of oxidized and wild type SOD1 are there is in secondary structure in SOD1, which is of a and two that may contribute to a a is in oxidized and SOD1 There is in the and in that the is in a similar in the oxidized and forms of SOD1. of have previously shown that of SOD1 are by MCO (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). Here, we a of the of oxidative results of oxidized and SOD1 are in and in are and well in with the that MCO produces to (16Stadtman E.R. Oliver C.N. J. Biol. Chem. 1991; 266: 2005-2008Abstract Full Text PDF PubMed Google Scholar). two and are also that there may be in SOD1. may be of a J. J. J.S. PubMed Scopus Google Scholar). in the of the SOD1 is also that the secondary structure of SOD1 changes upon there is of the structure to allow We have found that oxidation of type SOD1 at concentrations that have been in human results in aggregation in vitro. In fALS-associated mutant SODs at concentrations (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). Although oxidation of SOD1 not result in a to the secondary or tertiary structure, the structure is in prior to aggregation. The monomer intermediate is common to the aggregation of both wild type and fALS-associated mutant the structure is for proper enzymatic and L. M. R. M. 1998; PubMed Scopus Google A. S. L. A. A. G. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), this may for higher levels of oxidative stress in ALS patients (14Ferrante R.J. Browne S.E. Shinobu L.A. Bowling A.C. Baik M.J. MacGarvey U. Kowall N.W. Brown Jr., R.H. Beal M.F. J. Neurochem. 1997; 69: 2064-2074Crossref PubMed Scopus (655) Google Scholar) and of enzymatic activity in some fALS SOD1 mutants M. Y. Tanaka Y. T. E. S. T. M. J. Sci. 1994; Full Text PDF PubMed Scopus Google Scholar). We found that and aggregation results the oxidative modification of that are the of SOD1. small changes the oxidation of SOD1 in may cause the of monomers prior to which we to be the common intermediate in the of inclusion bodies in and of SOD1 a for the of in patients have inclusion bodies in their motor neurons. In mutant fALS, these are that for SOD1 D.W. Rothstein J.D. Rev. Neurosci. 2001; PubMed Scopus Google Scholar). fALS has been in in (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google T. S. K. R. T. M. S. Neurosci. Lett. 1998; PubMed Scopus Google Scholar) and in transgenic mouse models D.W. Rothstein J.D. Rev. Neurosci. 2001; PubMed Scopus Google Scholar). inclusion bodies in have These ubiquitin K. A. M. S. T. K. 2003; PubMed Scopus Google Scholar), a for and may SOD1 H.S. R. J. Sci. 1999; Full Text Full Text PDF PubMed Scopus Google S. N. T. T. Clin. 1996; Google N. A. M. S. Kato T. S. Z. T. A. T. K. Neurosci. Lett. 1994; PubMed Scopus Google Scholar). of wild type SOD1 is in at a subset of SOD1 may also be in some either because the SOD1 aggregates are small to be seen by or because SOD1 is by The inclusion then of proteins, either to or not to the which were by the of a of SOD1 caused by upon of these protein aggregates wild type SOD1 physiological has not been a model to the of wild type SOD1 aggregates in sporadic ALS is a model for is to because the in are The of proteins in patients (14Ferrante R.J. Browne S.E. Shinobu L.A. Bowling A.C. Baik M.J. MacGarvey U. Kowall N.W. Brown Jr., R.H. Beal M.F. J. Neurochem. 1997; 69: 2064-2074Crossref PubMed Scopus (655) Google Scholar) has to the that that may cause ALS is oxidative stress (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). We showed that fALS mutant SODs and SOD1 form visible aggregates at concentrations Here, wild type SOD1 is shown to form visible aggregates upon oxidation at concentrations similar to those found in the of motor neurons. provides a mechanism for the of wild type SOD1 aggregates in sporadic ALS. to fALS mutant SOD1, the higher concentrations of wild type SOD1 for in aggregation our finding of the aggregation propensity of mutant SOD1. The aggregation propensity of wild type SOD1 may then for the of compared with fALS D.W. PubMed Scopus Google Scholar). oxidation model of ALS that has a of with the number of oxidative which with a in SOD1 the of ALS by the aggregation propensity of the to and SOD1 a for the of and sporadic and familial ALS have clinical it has long been that there is some common pathological mechanism D.W. PubMed Scopus Google Scholar). The that both have possibly inclusion bodies has that fALS with SOD1 mutations the pathological mechanism both forms of the disease D.W. Rothstein J.D. Rev. Neurosci. 2001; PubMed Scopus Google Scholar). the physiologically of metal-catalyzed the and aggregation of both wild type and mutant SOD1 are at physiological the evidence for protein aggregation as a in ALS and the misfolding and of proteins in the aggregation pathway of other neurodegenerative we the pathological mechanism common to sporadic ALS with SOD1 inclusion bodies and fALS is the of we have that the SOD1 the aggregation propensity by mutant (11Rakhit R. Cunningham P. Furtos-Matei A. Dahan S. Qi X.F. Crow J.P. Cashman N.R. Kondejewski L.H. Chakrabartty A. J. Biol. Chem. 2002; 277: 47551-47556Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar) and then by wild type SOD1. type and mutant SODs may both a common oxidation-induced aggregation pathway that both and monomeric intermediate monomer may be because of high aggregation The in aggregation propensity is then caused by the of mutant SOD1, to wild which in the for the of the monomeric wild type SOD1 by of other proteins and it to a protein in of and aggregation J.P. Sampson J.B. Zhuang Y. Beckman J.S. J. Neurochem. 1997; 69: PubMed Scopus Google Scholar). The of this SOD1 aggregation model is in that SOD1 forms a monomer prior to aggregation the possibility that small that and the of SOD1 may be by the similar has been for the of familial amyloid T. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). in SOD1 in ALS and neurological disorders have protein aggregation as an of proteins have been found to be toxic to cell lines M. E. L. J. N. G. M. 2002; PubMed Scopus Google Scholar), whereas expression of such as chaperones and ubiquitin aggregation and cell viability (9Bruening W. Roy J. Giasson B. Figlewicz D.A. Mushynski W.E. Durham H.D. J. Neurochem. 1999; 72: 693-699Crossref PubMed Scopus (222) Google J. Ishigaki S. Hishikawa N. Yamamoto M. Doyu M. Murata S. Tanaka K. Taniguchi N. Sobue G. J. Biol. Chem. 2002; 277: 36793-36798Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). SOD1 inclusion bodies in ALS are with the protein aggregation hypothesis as the and ALS may be in the of diseases. The oxidation model of ALS has to the proposed pathological mechanism of familial amyloid is the implicated SOD1 exists in the same as with the destabilization of the protein to an monomeric intermediate W. Z. J. G.J. Protein Chem. 1997; PubMed Google Scholar). Our then that ALS and other misfolding may have common features with to aggregation and it may be to similar for this of diseases. We A. E. and Y. Zhuang for with