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Familial amyotrophic lateral sclerosis (FALS): Emerging hints from redox proteomics.
Free Radical Biology & Medicine 43 (2007) 157 – 159 www.elsevier.com/locate/freeradbiomed
Highlight Commentary
Familial amyotrophic lateral sclerosis (FALS): Emerging hints from redox proteomics. Highlight commentary on: “Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice—A model of familial amyotrophic lateral sclerosis”☆ Isabella Dalle-Donne ⁎ Department of Biology, University of Milan, via Celoria 26, I-20133 Milan, Italy Received 28 February 2007; revised 12 March 2007; accepted 19 March 2007 Available online 1 April 2007
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal, progressive adult-onset neurodegenerative disease without effective treatments to date, characterized by a selective death of the upper and lower motor neurons in the motor cortex, brain stem, and spinal cord, leading to muscle weakness and atrophy, progressive paralysis, and inexorable death, usually due to respiratory failure [1,2]. Approximately 50% of patients die within 3 years of onset of symptoms, and ∼90% die within 5 years, retaining intact their cognitive functions throughout the course of the disease. Approximately 90% of ALS cases are sporadic (SALS), whose etiology remains unknown. The remaining ∼10% of ALS cases are familial (heritable, FALS), which are clinically and histopathologically indistinguishable from the more common SALS. About 20% of FALS cases are caused by mutations in the gene encoding the antioxidant enzyme, cytosolic Cu,Zn-superoxide dismutase (SOD1) [3,4]. Over 100 different FALS-linked mutations in SOD1 have been identified [1,5], the most common
PII of original article: S0891-5849(05)00187-5. Abbreviations: ALS, amyotrophic lateral sclerosis; FALS, familial ALS; PD, Parkinson's disease; SALS, sporadic ALS; SOD1, Cu,Zn-superoxide dismutase; TCTP, translationally controlled tumor protein; UCH-L1, ubiquitin carboxyterminal hydrolase L-1. ☆ In an attempt to spotlight those Free Radical Biology & Medicine papers that seem to be exerting particularly significant influence on the field, this special “Highlights” section brings you commentaries about highly cited papers that we have published in the previous year. Citation information is provided by Elsevier's SCOPUS database; please visit www.SCOPUS.com for more details. ⁎ Fax: +39 02 50314781. E-mail address: [email protected]. 0891-5849/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.freeradbiomed.2007.03.029
being the A4V mutation (Val substituted for Ala at residue 4) and the G93A mutation (Ala substituted for Gly at residue 93) [5]. Transgenic mouse studies have demonstrated that mutant SOD1 toxicity is not essentially due to decreased dismutase activity, but rather to an unknown “gain of toxic function” [6], although the biochemical nature of this toxic gain of function is widely debated [2]. There are two main theories that might not be mutually exclusive: one suggests that the toxicity is due to misfolded aggregated forms of mutant SOD1 [1,7], whereas the other proposes that SOD1 becomes a prooxidant protein generating reactive oxygen and nitrogen species [2,8]. The subcellular etiology of ALS and the reason why aggregated SOD1 would be cytotoxic to motor neurons or the surrounding support cells remain unclear [9]. Selective motor neuron killing likely arises from a combination of several mechanisms, including protein misfolding and aggregation, oxidative stress/damage, apoptosis, proteasome inhibition, perturbations in mitochondrial function and Ca2+ homeostasis, and glutamate excitotoxicity [2,9]. Markers of oxidative damage were previously found in the cortex and spinal cords of patients with SALS and FALS as well as in transgenic mice (e.g., [6,10,11]). D. Allan Butterfield‘s lab was the first to use redox proteomics technology [12] to identify specific irreversibly oxidized, i.e., carbonylated, proteins in the mutant G93A-SOD1 FALS mouse model, which exhibits many of the hallmarks of human FALS. In the paper highlighted in this commentary [13], which has been identified as one of the most highly cited papers for 2005/2006 in “Free Radical Biology & MedicineTT by the
158
I. Dalle-Donne / Free Radical Biology & Medicine 43 (2007) 157–159
SCOPUS database (www.SCOPUS.com), Butterfield and colleagues unambiguously identified SOD1, translationally controlled tumor protein (TCTP), and ubiquitin carboxy-terminal hydrolase L-1 (UCH-L1) as carbonylated proteins in the spinal cord of symptomatic G93A-SOD1 mice, in which they also demonstrated loss of UCH-L1 activity [13]. Findings described in this paper [13] could provide important clues for deciphering potential molecular mechanism(s) of ALS pathogenesis, leading to neurodegeneration. The confirmation, by redox proteomics, of SOD1 carbonylation in spinal cord of G93A-SOD1 mice could be a further step in the understanding of the mechanism(s) at the basis of SOD1 aggregation, about which presently very little is known [2,9]. Proteinaceous inclusions rich in mutant SOD1 have been found in tissues from FALS patients, mutant SOD1 animals, and cellular models [14]. Furthermore, SOD1 is moderately oligoubiquitinated in spinal cord of symptomatic G93A-SOD1 mice [15]. SOD1 oxidation could also be related to the decreased antioxidant activity of the protein demonstrated in FALS patients [16]. Carbonylation and decreased activity of UCH-L1, a neuronal de-ubiquitinating enzyme crucial for proteasomal protein degradation and comprising ≤2% of total brain proteins, is consistent with the evidence of an impaired protein quality control in mutant SOD1-linked FALS [2,17]. Spinal cord of mutant SOD1 transgenic mice shows early reduction in protein chaperoning and activity of the ubiquitin-proteasome system [17]. Proteasomal dysfunction is a common feature of most neurodegenerative diseases, including ALS [18,19], where proteasome activity may be decreased by aggregates of mutant SOD1 in FALS [20]. UCHL1 has been shown to be carbonylated as well as dysfunctional in the brains from both sporadic [21] and familial [22] Alzheimer's disease (AD) subjects. Furthermore, UCH-L1 missense mutation causes an early-onset familial Parkinson's disease (PD) and several inherited forms of PD involve defects in the ubiquitin–proteasome system [18,19]. TCTP is endowed with multiple biological activities, including calcium binding, cell growth, and antiapoptotic functions, which collectively exert a protective role for cells. The observed carbonylation of TCTP in the spinal cord of G93A-SOD1 mice could be related to the mitochondrial dysfunction and altered calcium homeostasis occurring in ALS [2]. Oxidation and aggregated protein complexes have a role in the pathogenesis of neurodegenerative disorders [18,19,23,24]. However, the relationship among protein oxidation, protein aggregation, and neurodegeneration remains at present unclear [18,23,24]. The study of Butterfield and colleagues [13] is a valuable contribution to the possible reconciliation of the two current main theories of ALS pathogenesis, i.e., protein aggregation and oxidative damage [1,2,7,8]. This paper provides insights into the mechanism of G93A-SOD1 neurotoxicity, suggesting a potential relationship among protein oxidation, protein aggregation, and Ca2+ homeostasis regulation in ALS. In this respect, recent findings suggest direct links among protein oxidation, protein aggregation, mitochondrial damage, and FALS [25]. Further results from Butterfield's lab support the role of
oxidative stress as a major mechanism in the pathogenesis of ALS [26]. In view of the recent advancements in redox proteomics [12,27], a comprehensive analysis of all the protein targets of oxidative damage in ALS seems feasible. This would better define the role of protein oxidation and aggregation in ALS and help disclose the molecular basis of this devastating pathology. Neurodegenerative diseases are a major global health burden in the Western world, mainly because of our ageing population. Diseases such as ALS exert a great human toll on the affected individuals, their families, and society. Research into these disorders is therefore of great importance, and the oxidatively modified proteins identified in the paper by Butterfield and colleagues [13] could also be explored as potential therapeutic targets for FALS linked to SOD1 mutations. References [1] Valentine, J. S.; Doucette, P. A.; Potter, S. Z. Copper–zinc superoxide dismutases and amyotrophic lateral sclerosis. Annu. Rev. Biochem. 74: 563–593; 2005. [2] Pasinelli, P.; Brown, R. H. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat. Rev. Neurosci. 7:710–723; 2006. [3] Deng, H. X.; Hentati, A.; Tainer, J. A.; Iqbal, Z.; Cayabyab, A.; Hung, W. Y.; Getzoff, E. D.; Hu, P.; Herzfeldt, B.; Roos, R. P.; Warner, C.; Deng, G.; Soriano, E.; Smyth, C.; Parge, H. E.; Ahmed, A.; Roses, A. D.; Hallewell, R. A.; Pericak-Vance, M. A.; Siddique, T. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 20:1047–1051; 1993. [4] Rosen, D. R.; Siddique, T.; Patterson, D.; Figlewicz, D. A.; Sapp, P.; Hentati, A.; Donaldson, D.; Goto, J.; O'Regan, J. P.; Deng, H. X.; et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62; 1993. [5] Cudkowicz, M. E.; McKena-Yaske, R. N.; Sapp, P. E.; Chin, W.; Geller, B. S.; Hayden, D. L.; Schoenfeld, D. A.; Hosler, B. A.; Horvitz, H. R.; Brown, R. H. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann. Neurol. 41:210–221; 1997. [6] Cleveland, D. W.; Rothstein, J. D. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat. Rev. Neurosci. 2:806–819; 2001. [7] Valentine, J. S.; Hart, P. J. Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 100:3617–3622; 2003. [8] Barnham, K. J.; Masters, C. L.; Bush, A. I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov. 3:205–214; 2004. [9] Boillee, S.; Vande Velde, C.; Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59; 2006. [10] Beal, M. F.; Ferrante, R. J.; Browne, S. E.; Matthews, R. T.; Kowall, N. W.; Brown, R. H., Jr. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann. Neurol. 42:644–654; 1997. [11] Bruijn, L. I.; Beal, M. F.; Becher, M. W.; Schulz, J. B.; Wong, P. C.; Price, D. L.; Cleveland, D. W. Elevated free nitrotyrosine levels, but not proteinbound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. Proc. Natl. Acad. Sci. USA 94:7606–7611; 1997. [12] Dalle-Donne, I.; Scaloni, A.; Butterfield, D. A., eds. Redox Proteomics: from Protein Modifications to Cellular Dysfunction and Diseases. Hoboken, NJ: John Wiley & Sons, Inc.; 2006. [13] Poon, H. F.; Hensley, K.; Thongboonkerd, V.; Merchant, M. L.; Lynn, B. C.; Pierce, W. M.; Klein, J. B.; Calabrese, V.; Butterfield, D. A. Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice—A model of familial amyotrophic lateral sclerosis. Free Radic. Biol. Med. 39:453–462; 2005.
I. Dalle-Donne / Free Radical Biology & Medicine 43 (2007) 157–159 [14] Bruns, C. K.; Kopito, R. R. Impaired post-translational folding of familial ALS-linked Cu,Zn superoxide dismutase mutants. EMBO J. 26:855–866; 2007. [15] Basso, M.; Massignan, T.; Samengo, G.; Cheroni, C.; De Biasi, S.; Salmona, M.; Bendotti, C.; Bonetto, V. Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J. Biol. Chem. 281:33325–33335; 2006. [16] Browne, S. E.; Bowling, A. C.; Baik, M. J.; Gurney, M.; Brown, R. H., Jr.; Beal, M. F. Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. J. Neurochem. 71:281–287; 1998. [17] Kabashi, E.; Durham, H. D. Failure of protein quality control in amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1762:1038–1050; 2006. [18] Bossy-Wetzel, E.; Schwarzenbacher, R.; Lipton, S. A. Molecular pathways to neurodegeneration. Nat. Med. 10:S2–S9; 2004. [19] Halliwell, B. Proteasomal dysfunction: a common feature of neurodegenerative diseases? Implications for the environmental origins of neurodegeneration. Antioxid. Redox Signal. 8:2007–2019; 2006. [20] Cheroni, C.; Peviani, M.; Cascio, P.; De Biasi, S.; Monti, C.; Bendotti, C. Accumulation of human SOD1 and ubiquitinated deposits in the spinal cord of SOD1G93A mice during motor neuron disease progression correlates with a decrease of proteasome. Neurobiol. Dis. 18:509–522; 2005. [21] Castegna, A.; Aksenov, M.; Aksenova, M.; Thongboonkerd, V.; Klein, J. B.; Pierce, W. M.; Booze, R.; Markesbery, W. R.; Butterfield, D. A. Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part I: Creatine kinase BB, glutamine synthase, and ubiquitin
[22]
[23]
[24] [25]
[26]
[27]
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carboxy-terminal hydrolase L-1. Free Radic. Biol. Med. 33:562–571; 2002. Butterfield, D. A.; Gnjec, A.; Poon, H. F.; Castegna, A.; Pierce, W. M.; Klein, J. B.; Martins, R. N. Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer's disease: an initial assessment. J. Alzheimers Dis. 10:391–397; 2006. Butterfield, D. A.; Kanski, J. Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech. Ageing Dev. 122:945–962; 2001. Beal, M. F. Oxidatively modified proteins in aging and disease. Free Radic. Biol. Med. 32:797–803; 2002. Deng, H. X.; Shi, Y.; Furukawa, Y.; Zhai, H.; Fu, R.; Liu, E.; Gorrie, G. H.; Khan, M. S.; Hung, W. Y.; Bigio, E. H.; Lukas, T.; Dal Canto, M. C.; O'Halloran, T. V.; Siddique, T. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc. Natl. Acad. Sci. USA 103:7142–7147; 2006. Perluigi, M.; Fai Poon, H.; Hensley, K.; Pierce, W. M.; Klein, J. B.; Calabrese, V.; De Marco, C.; Butterfield, D. A. Proteomic analysis of 4hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice—a model of familial amyotrophic lateral sclerosis. Free Radic. Biol. Med. 38: 960–968; 2005. Dalle-Donne, I.; Scaloni, A.; Giustarini, D.; Cavarra, E.; Tell, G.; Lungarella, G.; Colombo, R.; Rossi, R.; Milzani, A. Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics. Mass Spectrom. Rev. 24:55–99; 2005.
Highlight Commentary
Familial amyotrophic lateral sclerosis (FALS): Emerging hints from redox proteomics. Highlight commentary on: “Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice—A model of familial amyotrophic lateral sclerosis”☆ Isabella Dalle-Donne ⁎ Department of Biology, University of Milan, via Celoria 26, I-20133 Milan, Italy Received 28 February 2007; revised 12 March 2007; accepted 19 March 2007 Available online 1 April 2007
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal, progressive adult-onset neurodegenerative disease without effective treatments to date, characterized by a selective death of the upper and lower motor neurons in the motor cortex, brain stem, and spinal cord, leading to muscle weakness and atrophy, progressive paralysis, and inexorable death, usually due to respiratory failure [1,2]. Approximately 50% of patients die within 3 years of onset of symptoms, and ∼90% die within 5 years, retaining intact their cognitive functions throughout the course of the disease. Approximately 90% of ALS cases are sporadic (SALS), whose etiology remains unknown. The remaining ∼10% of ALS cases are familial (heritable, FALS), which are clinically and histopathologically indistinguishable from the more common SALS. About 20% of FALS cases are caused by mutations in the gene encoding the antioxidant enzyme, cytosolic Cu,Zn-superoxide dismutase (SOD1) [3,4]. Over 100 different FALS-linked mutations in SOD1 have been identified [1,5], the most common
PII of original article: S0891-5849(05)00187-5. Abbreviations: ALS, amyotrophic lateral sclerosis; FALS, familial ALS; PD, Parkinson's disease; SALS, sporadic ALS; SOD1, Cu,Zn-superoxide dismutase; TCTP, translationally controlled tumor protein; UCH-L1, ubiquitin carboxyterminal hydrolase L-1. ☆ In an attempt to spotlight those Free Radical Biology & Medicine papers that seem to be exerting particularly significant influence on the field, this special “Highlights” section brings you commentaries about highly cited papers that we have published in the previous year. Citation information is provided by Elsevier's SCOPUS database; please visit www.SCOPUS.com for more details. ⁎ Fax: +39 02 50314781. E-mail address: [email protected]. 0891-5849/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.freeradbiomed.2007.03.029
being the A4V mutation (Val substituted for Ala at residue 4) and the G93A mutation (Ala substituted for Gly at residue 93) [5]. Transgenic mouse studies have demonstrated that mutant SOD1 toxicity is not essentially due to decreased dismutase activity, but rather to an unknown “gain of toxic function” [6], although the biochemical nature of this toxic gain of function is widely debated [2]. There are two main theories that might not be mutually exclusive: one suggests that the toxicity is due to misfolded aggregated forms of mutant SOD1 [1,7], whereas the other proposes that SOD1 becomes a prooxidant protein generating reactive oxygen and nitrogen species [2,8]. The subcellular etiology of ALS and the reason why aggregated SOD1 would be cytotoxic to motor neurons or the surrounding support cells remain unclear [9]. Selective motor neuron killing likely arises from a combination of several mechanisms, including protein misfolding and aggregation, oxidative stress/damage, apoptosis, proteasome inhibition, perturbations in mitochondrial function and Ca2+ homeostasis, and glutamate excitotoxicity [2,9]. Markers of oxidative damage were previously found in the cortex and spinal cords of patients with SALS and FALS as well as in transgenic mice (e.g., [6,10,11]). D. Allan Butterfield‘s lab was the first to use redox proteomics technology [12] to identify specific irreversibly oxidized, i.e., carbonylated, proteins in the mutant G93A-SOD1 FALS mouse model, which exhibits many of the hallmarks of human FALS. In the paper highlighted in this commentary [13], which has been identified as one of the most highly cited papers for 2005/2006 in “Free Radical Biology & MedicineTT by the
158
I. Dalle-Donne / Free Radical Biology & Medicine 43 (2007) 157–159
SCOPUS database (www.SCOPUS.com), Butterfield and colleagues unambiguously identified SOD1, translationally controlled tumor protein (TCTP), and ubiquitin carboxy-terminal hydrolase L-1 (UCH-L1) as carbonylated proteins in the spinal cord of symptomatic G93A-SOD1 mice, in which they also demonstrated loss of UCH-L1 activity [13]. Findings described in this paper [13] could provide important clues for deciphering potential molecular mechanism(s) of ALS pathogenesis, leading to neurodegeneration. The confirmation, by redox proteomics, of SOD1 carbonylation in spinal cord of G93A-SOD1 mice could be a further step in the understanding of the mechanism(s) at the basis of SOD1 aggregation, about which presently very little is known [2,9]. Proteinaceous inclusions rich in mutant SOD1 have been found in tissues from FALS patients, mutant SOD1 animals, and cellular models [14]. Furthermore, SOD1 is moderately oligoubiquitinated in spinal cord of symptomatic G93A-SOD1 mice [15]. SOD1 oxidation could also be related to the decreased antioxidant activity of the protein demonstrated in FALS patients [16]. Carbonylation and decreased activity of UCH-L1, a neuronal de-ubiquitinating enzyme crucial for proteasomal protein degradation and comprising ≤2% of total brain proteins, is consistent with the evidence of an impaired protein quality control in mutant SOD1-linked FALS [2,17]. Spinal cord of mutant SOD1 transgenic mice shows early reduction in protein chaperoning and activity of the ubiquitin-proteasome system [17]. Proteasomal dysfunction is a common feature of most neurodegenerative diseases, including ALS [18,19], where proteasome activity may be decreased by aggregates of mutant SOD1 in FALS [20]. UCHL1 has been shown to be carbonylated as well as dysfunctional in the brains from both sporadic [21] and familial [22] Alzheimer's disease (AD) subjects. Furthermore, UCH-L1 missense mutation causes an early-onset familial Parkinson's disease (PD) and several inherited forms of PD involve defects in the ubiquitin–proteasome system [18,19]. TCTP is endowed with multiple biological activities, including calcium binding, cell growth, and antiapoptotic functions, which collectively exert a protective role for cells. The observed carbonylation of TCTP in the spinal cord of G93A-SOD1 mice could be related to the mitochondrial dysfunction and altered calcium homeostasis occurring in ALS [2]. Oxidation and aggregated protein complexes have a role in the pathogenesis of neurodegenerative disorders [18,19,23,24]. However, the relationship among protein oxidation, protein aggregation, and neurodegeneration remains at present unclear [18,23,24]. The study of Butterfield and colleagues [13] is a valuable contribution to the possible reconciliation of the two current main theories of ALS pathogenesis, i.e., protein aggregation and oxidative damage [1,2,7,8]. This paper provides insights into the mechanism of G93A-SOD1 neurotoxicity, suggesting a potential relationship among protein oxidation, protein aggregation, and Ca2+ homeostasis regulation in ALS. In this respect, recent findings suggest direct links among protein oxidation, protein aggregation, mitochondrial damage, and FALS [25]. Further results from Butterfield's lab support the role of
oxidative stress as a major mechanism in the pathogenesis of ALS [26]. In view of the recent advancements in redox proteomics [12,27], a comprehensive analysis of all the protein targets of oxidative damage in ALS seems feasible. This would better define the role of protein oxidation and aggregation in ALS and help disclose the molecular basis of this devastating pathology. Neurodegenerative diseases are a major global health burden in the Western world, mainly because of our ageing population. Diseases such as ALS exert a great human toll on the affected individuals, their families, and society. Research into these disorders is therefore of great importance, and the oxidatively modified proteins identified in the paper by Butterfield and colleagues [13] could also be explored as potential therapeutic targets for FALS linked to SOD1 mutations. References [1] Valentine, J. S.; Doucette, P. A.; Potter, S. Z. Copper–zinc superoxide dismutases and amyotrophic lateral sclerosis. Annu. Rev. Biochem. 74: 563–593; 2005. [2] Pasinelli, P.; Brown, R. H. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat. Rev. Neurosci. 7:710–723; 2006. [3] Deng, H. X.; Hentati, A.; Tainer, J. A.; Iqbal, Z.; Cayabyab, A.; Hung, W. Y.; Getzoff, E. D.; Hu, P.; Herzfeldt, B.; Roos, R. P.; Warner, C.; Deng, G.; Soriano, E.; Smyth, C.; Parge, H. E.; Ahmed, A.; Roses, A. D.; Hallewell, R. A.; Pericak-Vance, M. A.; Siddique, T. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 20:1047–1051; 1993. [4] Rosen, D. R.; Siddique, T.; Patterson, D.; Figlewicz, D. A.; Sapp, P.; Hentati, A.; Donaldson, D.; Goto, J.; O'Regan, J. P.; Deng, H. X.; et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62; 1993. [5] Cudkowicz, M. E.; McKena-Yaske, R. N.; Sapp, P. E.; Chin, W.; Geller, B. S.; Hayden, D. L.; Schoenfeld, D. A.; Hosler, B. A.; Horvitz, H. R.; Brown, R. H. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann. Neurol. 41:210–221; 1997. [6] Cleveland, D. W.; Rothstein, J. D. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat. Rev. Neurosci. 2:806–819; 2001. [7] Valentine, J. S.; Hart, P. J. Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 100:3617–3622; 2003. [8] Barnham, K. J.; Masters, C. L.; Bush, A. I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov. 3:205–214; 2004. [9] Boillee, S.; Vande Velde, C.; Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59; 2006. [10] Beal, M. F.; Ferrante, R. J.; Browne, S. E.; Matthews, R. T.; Kowall, N. W.; Brown, R. H., Jr. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann. Neurol. 42:644–654; 1997. [11] Bruijn, L. I.; Beal, M. F.; Becher, M. W.; Schulz, J. B.; Wong, P. C.; Price, D. L.; Cleveland, D. W. Elevated free nitrotyrosine levels, but not proteinbound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. Proc. Natl. Acad. Sci. USA 94:7606–7611; 1997. [12] Dalle-Donne, I.; Scaloni, A.; Butterfield, D. A., eds. Redox Proteomics: from Protein Modifications to Cellular Dysfunction and Diseases. Hoboken, NJ: John Wiley & Sons, Inc.; 2006. [13] Poon, H. F.; Hensley, K.; Thongboonkerd, V.; Merchant, M. L.; Lynn, B. C.; Pierce, W. M.; Klein, J. B.; Calabrese, V.; Butterfield, D. A. Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice—A model of familial amyotrophic lateral sclerosis. Free Radic. Biol. Med. 39:453–462; 2005.
I. Dalle-Donne / Free Radical Biology & Medicine 43 (2007) 157–159 [14] Bruns, C. K.; Kopito, R. R. Impaired post-translational folding of familial ALS-linked Cu,Zn superoxide dismutase mutants. EMBO J. 26:855–866; 2007. [15] Basso, M.; Massignan, T.; Samengo, G.; Cheroni, C.; De Biasi, S.; Salmona, M.; Bendotti, C.; Bonetto, V. Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J. Biol. Chem. 281:33325–33335; 2006. [16] Browne, S. E.; Bowling, A. C.; Baik, M. J.; Gurney, M.; Brown, R. H., Jr.; Beal, M. F. Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. J. Neurochem. 71:281–287; 1998. [17] Kabashi, E.; Durham, H. D. Failure of protein quality control in amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1762:1038–1050; 2006. [18] Bossy-Wetzel, E.; Schwarzenbacher, R.; Lipton, S. A. Molecular pathways to neurodegeneration. Nat. Med. 10:S2–S9; 2004. [19] Halliwell, B. Proteasomal dysfunction: a common feature of neurodegenerative diseases? Implications for the environmental origins of neurodegeneration. Antioxid. Redox Signal. 8:2007–2019; 2006. [20] Cheroni, C.; Peviani, M.; Cascio, P.; De Biasi, S.; Monti, C.; Bendotti, C. Accumulation of human SOD1 and ubiquitinated deposits in the spinal cord of SOD1G93A mice during motor neuron disease progression correlates with a decrease of proteasome. Neurobiol. Dis. 18:509–522; 2005. [21] Castegna, A.; Aksenov, M.; Aksenova, M.; Thongboonkerd, V.; Klein, J. B.; Pierce, W. M.; Booze, R.; Markesbery, W. R.; Butterfield, D. A. Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part I: Creatine kinase BB, glutamine synthase, and ubiquitin
[22]
[23]
[24] [25]
[26]
[27]
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carboxy-terminal hydrolase L-1. Free Radic. Biol. Med. 33:562–571; 2002. Butterfield, D. A.; Gnjec, A.; Poon, H. F.; Castegna, A.; Pierce, W. M.; Klein, J. B.; Martins, R. N. Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer's disease: an initial assessment. J. Alzheimers Dis. 10:391–397; 2006. Butterfield, D. A.; Kanski, J. Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech. Ageing Dev. 122:945–962; 2001. Beal, M. F. Oxidatively modified proteins in aging and disease. Free Radic. Biol. Med. 32:797–803; 2002. Deng, H. X.; Shi, Y.; Furukawa, Y.; Zhai, H.; Fu, R.; Liu, E.; Gorrie, G. H.; Khan, M. S.; Hung, W. Y.; Bigio, E. H.; Lukas, T.; Dal Canto, M. C.; O'Halloran, T. V.; Siddique, T. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc. Natl. Acad. Sci. USA 103:7142–7147; 2006. Perluigi, M.; Fai Poon, H.; Hensley, K.; Pierce, W. M.; Klein, J. B.; Calabrese, V.; De Marco, C.; Butterfield, D. A. Proteomic analysis of 4hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice—a model of familial amyotrophic lateral sclerosis. Free Radic. Biol. Med. 38: 960–968; 2005. Dalle-Donne, I.; Scaloni, A.; Giustarini, D.; Cavarra, E.; Tell, G.; Lungarella, G.; Colombo, R.; Rossi, R.; Milzani, A. Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics. Mass Spectrom. Rev. 24:55–99; 2005.