Bis(thiosemicarbazone) metal complexes as therapeutics for neurodegenerative diseases

Current Topics in Medicinal Chemistry

Volumn 16, Issue 27, 2016, Pages 3058-3068

  McKenzie Nickson, S ^a,b   Bush, A I ^a   Barnham, K J ^a,b  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

AD; ALS; Bis(thiosemicarbazone); BTSC; CuII(atsm); CUII(gtsm)

Indexed keywords

COPPER; DOPA; DOPAMINE; LEVODOPA; METAL COMPLEX; REACTIVE OXYGEN METABOLITE; THIOSEMICARBAZONE; THIOSEMICARBAZONE METAL COMPLEX; UNCLASSIFIED DRUG; ZINC; COORDINATION COMPOUND; METAL; THIOSEMICARBAZONE DERIVATIVE;

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; BLOOD BRAIN BARRIER; COGNITIVE DEFECT; CONFUSION; DEGENERATIVE DISEASE; DRUG BIOAVAILABILITY; DRUG EFFICACY; GENE MUTATION; HALLUCINATION; HUMAN; NAUSEA; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; REVIEW; SLEEP DISORDER; ANIMAL; CHEMISTRY; NEURODEGENERATIVE DISEASES;

ANIMALS; COORDINATION COMPLEXES; HUMANS; METALS; NEURODEGENERATIVE DISEASES; THIOSEMICARBAZONES;

EID: 84989244226     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026616666160216155746     Document Type: Review

References (151)

1. Woimant, F.; Trocello, J.-M. Disorders of Heavy Metals. Handb. Clin. Neurol. 2014, 120, 851-864.
2. Jomova, K.; Valko, M. Advances in Metal-Induced Oxidative Stress and Human Disease. Toxicology, 2011, 283 (2-3), 65-87.
3. Rivera-Mancía, S.; Pérez-Neri, I.; Ríos, C.; Tristán-López, L.; Rivera-Espinosa, L.; Montes, S. The Transition Metals Copper and Iron in Neurodegenerative Diseases. Chem. Biol. Interact., 2010, 186 (2), 184-199.
4. Breydo, L.; Uversky, V. N. Role of Metal Ions in Aggregation of Intrinsically Disordered Proteins in Neurodegenerative Diseases. Met. Integr. Biometal Sci., 2011, 3 (11), 1163-1180.
5. Ward, R. J.; Zucca, F. A.; Duyn, J. H.; Crichton, R. R.; Zecca, L. The Role of Iron in Brain Ageing and Neurodegenerative Disorders. Lancet Neurol., 2014, 13 (10), 1045-1060.
6. Ward, R. J.; Dexter, D. T.; Crichton, R. R. Chelating Agents for Neurodegenerative Diseases. Curr. Med. Chem., 2012, 19 (17), 2760-2772.
7. Mot, A. I.; Wedd, A. G.; Sinclair, L.; Brown, D. R.; Collins, S. J.; Brazier, M. W. Metal Attenuating Therapies in Neurodegenerative Disease. Expert Rev. Neurother., 2011, 11 (12), 1717-1745.
8. Hung, L. W.; Barnham, K. J. Modulating Metals as a Therapeutic Strategy for Alzheimer’s Disease. Future Med. Chem., 2012, 4 (8), 955-969.
9. Crouch, P. J.; Barnham, K. J. Therapeutic Redistribution of Metal Ions To Treat Alzheimer’s Disease. Acc. Chem. Res., 2012, 45 (9), 1604-1611.
10. Barnham, K. J.; Bush, A. I. Metals in Alzheimer’s and Parkinson’s Diseases. Curr. Opin. Chem. Biol., 2008, 12 (2), 222-228.
11. Barnham, K. J.; Bush, A. I. Biological Metals and Metal-Targeting Compounds in Major Neurodegenerative Diseases. Chem. Soc. Rev., 2014.
12. Donnelly, P. S.; Caragounis, A.; Du, T.; Laughton, K. M.; Volitakis, I.; Cherny, R. A.; Sharples, R. A.; Hill, A. F.; Li, Q.-X.; Masters, C. L.; Barnham, K. J.; White, A. R. Selective Intracellular Release of Copper and Zinc Ions from Bis(thiosemicarbazonato) Complexes Reduces Levels of Alzheimer Disease Amyloid- Peptide. J. Biol. Chem., 2007, 283 (8), 4568-4577.
13. Xiao, Z.; Donnelly, P. S.; Zimmermann, M.; Wedd, A. G. Transfer of Copper between Bis(thiosemicarbazone) Ligands and Intracellular Copper-Binding Proteins. Insights into Mechanisms of Copper Uptake and Hypoxia Selectivity. Inorg. Chem., 2008, 47 (10), 4338-4347.
14. Price, K. A.; Crouch, P. J.; Volitakis, I.; Paterson, B. M.; Lim, S.; Donnelly, P. S.; White, A. R. Mechanisms Controlling the Cellular Accumulation of Copper Bis(thiosemicarbazonato) Complexes. Inorg. Chem., 2011, 50 (19), 9594-9605.
15. Fodero-Tavoletti, M. T.; Villemagne, V. L.; Paterson, B. M.; White, A. R.; Li, Q.-X.; Camakaris, J.; O’Keefe, G.; Cappai, R.; Barnham, K. J.; Donnelly, P. S. Bis (thiosemicarbazonato) Cu-64 Complexes for Positron Emission Tomography Imaging of Alzheimer’s Disease. J. Alzheimers Dis., 2010, 20 (1), 49-55.
16. Bourgeois, M.; Rajerison, H.; Guerard, F.; Mougin-Degraef, M.; Barbet, J.; Michel, N.; Cherel, M.; Faivre-Chauvet, A. Contribution of [64Cu]-ATSM PET in Molecular Imaging of Tumour Hypoxia Compared to Classical [18F]-MISO--a Selected Review. Nucl. Med. Rev. Cent. East. Eur., 2011, 14 (2), 90-95.
17. Paterson, B. M.; Donnelly, P. S. Copper Complexes of Bis(thiosemicarbazones): From Chemotherapeutics to Diagnostic and Therapeutic Radiopharmaceuticals. Chem. Soc. Rev., 2011, 40 (5), 3005-3018.
18. Holland, J. P.; Lewis, J. S.; Dehdashti, F. Assessing Tumor Hypoxia by Positron Emission Tomography with Cu-ATSM. Q. J. Nucl. Med. Mol. Imaging Off. Publ. Ital. Assoc. Nucl. Med. AIMN Int. Assoc. Radiopharmacol. IAR Sect. Soc. Radiopharm. Chem. Biol., 2009, 53 (2), 193-200.
19. Lapi, S. E.; Lewis, J. S.; Dehdashti, F. Evaluation of Hypoxia With Copper-Labeled Diacetyl-bis(N-Methylthiosemicarbazone). Semin. Nucl. Med., 2015, 45 (2), 177-185.
20. Petering, H. G.; Buskirk, H. H.; Underwood, G. E. The Anti-Tumor Activity of 2-Keto-3-Ethoxybutyraldehyde Bis(thiosemicarbazone) and Related Compounds. Cancer Res., 1964, 24 (3 Part 1), 367-372.
21. Petering, D. H. Physico-Chemical Properties of the Antitumor Agent, 3-Ethoxy-2-Oxobutyraldehyde Bis (thiosemicarbazonato) copper(II). Bioinorg. Chem., 1972, 1 (4), 255-271.
22. Dearling, J. L.; Lewis, J. S.; Mullen, G. E.; Welch, M. J.; Blower, P. J. Copper Bis(thiosemicarbazone) Complexes as Hypoxia Imaging Agents: Structure-Activity Relationships. JBIC J. Biol. Inorg. Chem., 2002, 7 (3), 249-259.
23. Dearling, J. L.; Lewis, J. S.; Mullen, G. E.; Rae, M. T.; Zweit, J.; Blower, P. J. Design of Hypoxia-Targeting Radiopharmaceuticals: Selective Uptake of Copper-64 Complexes in Hypoxic Cells in Vitro. Eur. J. Nucl. Med., 1998, 25 (7), 788-792.
24. Lewis, J.; Laforest, R.; Buettner, T.; Song, S.; Fujibayashi, Y.; Connett, J.; Welch, M. Copper-64-Diacetyl-bis(N4-Methylthiosemicarbazone): An Agent for Radiotherapy. Proc. Natl. Acad. Sci. U. S. A., 2001, 98 (3), 1206-1211.
25. Alzheimer, A.; Stelzmann, R. A.; Schnitzlein, H. N.; Murtagh, F. R. An English Translation of Alzheimer’s 1907 Paper, "Uber Eine Eigenartige Erkankung Der Hirnrinde." Clin. Anat. N. Y. N., 1995, 8 (6), 429-431.
26. Skillbäck, T.; Farahmand, B. Y.; Rosén, C.; Mattsson, N.; Nägga, K.; Kilander, L.; Religa, D.; Wimo, A.; Winblad, B.; Schott, J. M.; Blennow, K.; Eriksdotter, M.; Zetterberg, H. Cerebrospinal Fluid Tau and Amyloid-β1-42 in Patients with Dementia. Brain, 2015, 138 (9), 2716-2731.
27. Selkoe, D. J. Alzheimer’s Disease Is a Synaptic Failure. Science, 2002, 298 (5594), 789-791.
28. Sensi, S. L.; Paoletti, P.; Koh, J.-Y.; Aizenman, E.; Bush, A. I.; Hershfinkel, M. The Neurophysiology and Pathology of Brain Zinc. J. Neurosci., 2011, 31 (45), 16076-16085.
29. Smart, T. G. Zn2+ Ions: Modulators of Excitatory and Inhibitory Synaptic Activity. Neuroscientist, 2004, 10 (5), 432-442.
30. Adlard, P. A.; Parncutt, J. M.; Finkelstein, D. I.; Bush, A. I. Cognitive Loss in Zinc Transporter-3 Knock-Out Mice: A Phenocopy for the Synaptic and Memory Deficits of Alzheimer’s Disease? J. Neurosci., 2010, 30 (5), 1631-1636.
31. Schlief, M. L.; Gitlin, J. D. Copper Homeostasis in the CNS. Mol. Neurobiol., 2006, 33 (2), 81-90.
32. Lutsenko, S.; Petris, M. J. Function and Regulation of the Mammalian Copper-Transporting ATPases: Insights from Biochemical and Cell Biological Approaches. J. Membr. Biol., 2003, 191 (1), 1-12.
33. Madarić, A.; Ginter, E.; Kadrabová, J. Serum Copper, Zinc and Copper/zinc Ratio in Males: Influence of Aging. Physiol. Res. Acad. Sci. Bohemoslov., 1994, 43 (2), 107-111.
34. Martínez Lista, E.; Solé, J.; Arola, L.; Mas, A. Changes in Plasma Copper and Zinc during Rat Development. Biol. Neonate, 1993, 64 (1), 47-52.
35. Maynard, C. J. Overexpression of Alzheimer’s Disease Amyloid-Beta Opposes the Age-Dependent Elevations of Brain Copper and Iron. J. Biol. Chem., 2002, 277 (47), 44670-44676.
36. Maynard, C. J.; Cappai, R.; Volitakis, I.; Cherny, R. A.; Masters, C. L.; Li, Q.-X.; Bush, A. I. Gender and Genetic Background Effects on Brain Metal Levels in APP Transgenic and Normal Mice: Implications for Alzheimer β -Amyloid Pathology. J. Inorg. Biochem., 2006, 100 (5-6), 952-962.
37. Mocchegiani, E.; Bertoni-Freddari, C.; Marcellini, F.; Malavolta, M. Brain, Aging and Neurodegeneration: Role of Zinc Ion Availability. Prog. Neurobiol., 2005, 75 (6), 367-390.
38. Goodman, L. Alzheimer’s Disease; a Clinico-Pathologic Analysis of Twenty-Three Cases with a Theory on Pathogenesis. J. Nerv. Ment. Dis., 1953, 118 (2), 97-130.
39. Lovell, M. A.; Robertson, J. D.; Teesdale, W. J.; Campbell, J. L.; Markesbery, W. R. Copper, Iron and Zinc in Alzheimer’s Disease Senile Plaques. J. Neurol. Sci., 1998, 158 (1), 47-52.
40. Grundke-Iqbal, I.; Fleming, J.; Tung, Y.-C.; Lassmann, H.; Iqbal, K.; Joshi, J. G. Ferritin Is a Component of the Neuritic (senile) Plaque in Alzheimer Dementia. Acta Neuropathol. (Berl.), 1990, 81 (2), 105-110.
41. Bouras, C.; Giannakopoulos, P.; Good, P. F.; Hsu, A.; Hof, P. R.; Perl, D. P. A Laser Microprobe Mass Analysis of Brain Aluminum and Iron in Dementia Pugilistica: Comparison with Alzheimer’s Disease. Eur. Neurol., 1997, 38 (1), 53-58.
42. LeVine, S. M. Iron Deposits in Multiple Sclerosis and Alzheimer’s Disease Brains. Brain Res., 1997, 760 (1-2), 298-303.
43. Connor, J. R.; Snyder, B. S.; Beard, J. L.; Fine, R. E.; Mufson, E. J. Regional Distribution of Iron and Iron-Regulatory Proteins in the Brain in Aging and Alzheimer’s Disease. J. Neurosci. Res., 1992, 31 (2), 327-335.
44. Robson, K. J. H. Synergy between the C2 Allele of Transferrin and the C282Y Allele of the Haemochromatosis Gene (HFE) as Risk Factors for Developing Alzheimer’s Disease. J. Med. Genet., 2004, 41 (4), 261-265.
45. Bertram, L.; McQueen, M. B.; Mullin, K.; Blacker, D.; Tanzi, R. E. Systematic Meta-Analyses of Alzheimer Disease Genetic Association Studies: The AlzGene Database. Nat. Genet., 2007, 39 (1), 17-23.
46. Mainous III, A. G.; Eschenbach, S. L.; Wells, B. J.; Everett, C. J.; Gill, J. M. Cholesterol, Transferrin Saturation, and the Development of Dementia and Alzheimer’s Disease: Results from an 18-Year Population-Based Cohort. Fam. Med., 2005, 37 (1), 36-42.
47. Cirrito, J. R.; Kang, J.-E.; Lee, J.; Stewart, F. R.; Verges, D. K.; Silverio, L. M.; Bu, G.; Mennerick, S.; Holtzman, D. M. Endocytosis Is Required for Synaptic Activity-Dependent Release of Amyloid-β In Vivo. Neuron, 2008, 58 (1), 42-51.
48. Terry, R. D. The Pathogenesis of Alzheimer Disease: An Alternative to the Amyloid Hypothesis. J. Neuropathol. Exp. Neurol., 1996, 55 (10), 1023-1025.
49. Lee, J.-Y.; Cole, T. B.; Palmiter, R. D.; Suh, S. W.; Koh, J.-Y. Contribution by Synaptic Zinc to the Gender-Disparate Plaque Formation in Human Swedish Mutant APP Transgenic Mice. Proc. Natl. Acad. Sci. U. S. A., 2002, 99 (11), 7705-7710.
50. Smith, D.; Cappai, R.; Barnham, K. The Redox Chemistry of the Alzheimer’s Disease Amyloid β Peptide. Biochim. Biophys. Acta BBA - Biomembr., 2007, 1768 (8), 1976-1990.
51. Bush, A. I. The Metallobiology of Alzheimer’s Disease. Trends Neurosci., 2003, 26 (4), 207-214.
52. Huang, X.; Atwood, C. S.; Hartshorn, M. A.; Multhaup, G.; Goldstein, L. E.; Scarpa, R. C.; Cuajungco, M. P.; Gray, D. N.; Lim, J.; Moir, R. D.; Tanzi, R. E.; Bush, A. I. The Aβ Peptide of Alzheimer’s Disease Directly Produces Hydrogen Peroxide through Metal Ion Reduction †. Biochemistry (Mosc.), 1999, 38 (24), 7609-7616.
53. Bush, A. I.; Pettingell, W. H.; Multhaup, G.; d Paradis, M.; Vonsattel, J.-P.; Gusella, J. F.; Beyreuther, K.; Masters, C. L.; Tanzi, R. E. Rapid Induction of Alzheimer A Beta Amyloid Formation by Zinc. Science, 1994, 265 (5177), 1464-1467.
54. Atwood, C. S.; Moir, R. D.; Huang, X.; Scarpa, R. C.; Bacarra, N. M. E.; Romano, D. M.; Hartshorn, M. A.; Tanzi, R. E.; Bush, A. I. Dramatic Aggregation of Alzheimer Aβ by Cu (II) Is Induced by Conditions Representing Physiological Acidosis. J. Biol. Chem., 1998, 273 (21), 12817-12826.
55. Butterfield, D. A.; Drake, J.; Pocernich, C.; Castegna, A. Evidence of Oxidative Damage in Alzheimer’s Disease Brain: Central Role for Amyloid β-Peptide. Trends Mol. Med., 2001, 7 (12), 548-554.
56. Barnham, K. J.; Masters, C. L.; Bush, A. I. Neurodegenerative Diseases and Oxidative Stress. Nat. Rev. Drug Discov.,,2004, 3 (3), 205-214.
57. Barnham, K. J. Tyrosine Gated Electron Transfer Is Key to the Toxic Mechanism of Alzheimer’s Disease -Amyloid. FASEB J., 2004.
58. Barnham, K. J. Neurotoxic, Redox-Competent Alzheimer’s -Amyloid Is Released from Lipid Membrane by Methionine Oxidation. J. Biol. Chem., 2003, 278 (44), 42959-42965.
59. Puglielli, L.; Friedlich, A. L.; Setchell, K. D. R.; Nagano, S.; Opazo, C.; Cherny, R. A.; Barnham, K. J.; Wade, J. D.; Melov, S.; Kovacs, D. M.; Bush, A. I. Alzheimer Disease β-Amyloid Activity Mimics Cholesterol Oxidase. J. Clin. Invest., 2005, 115 (9), 2556-2563.
60. Chen, K.; Kazachkov, M.; Yu, P. H. Effect of Aldehydes Derived from Oxidative Deamination and Oxidative Stress on β -Amyloid Aggregation; Pathological Implications to Alzheimer’s Disease. J. Neural Transm., 2007, 114 (6), 835-839.
61. Ali, F. E.; Separovic, F.; Barrow, C. J.; Cherny, R. A.; Fraser, F.; Bush, A. I.; Masters, C. L.; Barnham, K. J. Methionine Regulates Copper/hydrogen Peroxide Oxidation Products of Abeta. J. Pept. Sci. Off. Publ. Eur. Pept. Soc., 2005, 11 (6), 353-360.
62. Ali, F. E.; Leung, A.; Cherny, R. A.; Mavros, C.; Barnham, K. J.; Separovic, F.; Barrow, C. J. Dimerisation of N-Acetyl-L-Tyrosine Ethyl Ester and Abeta Peptides via Formation of Dityrosine. Free Radic. Res., 2006, 40 (1), 1-9.
63. Schöneich, C. Redox Processes of Methionine Relevant to β -Amyloid Oxidation and Alzheimer’s Disease. Arch. Biochem. Biophys., 2002, 397 (2), 370-376.
64. Atwood, C. S.; Perry, G.; Zeng, H.; Kato, Y.; Jones, W. D.; Ling, K.-Q.; Huang, X.; Moir, R. D.; Wang, D.; Sayre, L. M.; Smith, M. A.; Chen, S. G.; Bush, A. I. Copper Mediates Dityrosine Cross-Linking of Alzheimer’s Amyloid-β †. Biochemistry (Mosc.), 2004, 43 (2), 560-568.
65. Al-Hilaly, Y. K.; Williams, T. L.; Stewart-Parker, M.; Ford, L.; Skaria, E.; Cole, M.; Bucher, W. G.; Morris, K. L.; Sada, A. A.; Thorpe, J. R.; others. A Central Role for Dityrosine Crosslinking of Amyloid-β in Alzheimer’s Disease. Acta Neuropathol. Commun., 2013, 1 (83), 1-17.
66. Deibel, M. A.; Ehmann, W. D.; Markesbery, W. R. Copper, Iron, and Zinc Imbalances in Severely Degenerated Brain Regions in Alzheimer’s Disease: Possible Relation to Oxidative Stress. J. Neurol. Sci., 1996, 143 (1-2), 137-142.
67. Squitti, R.; Lupoi, D.; Pasqualetti, P.; Dal Forno, G.; Vernieri, F.; Chiovenda, P.; Rossi, L.; Cortesi, M.; Cassetta, E.; Rossini, P. M. Elevation of Serum Copper Levels in Alzheimer’s Disease. Neurology, 2002, 59 (8), 1153-1161.
68. Maynard, C. J.; Bush, A. I.; Masters, C. L.; Cappai, R.; Li, Q.-X. Metals and Amyloid-Beta in Alzheimer’s Disease. Int. J. Exp. Pathol., 2005, 86 (3), 147-159.
69. Crouch, P. J.; Hung, L. W.; Adlard, P. A.; Cortes, M.; Lal, V.; Filiz, G.; Perez, K. A.; Nurjono, M.; Caragounis, A.; Du, T. Increasing Cu Bioavailability Inhibits Aβ Oligomers and Tau Phosphorylation. Proc. Natl. Acad. Sci., 2009, 106 (2), 381-386.
70. Llorens-Marítin, M.; Jurado, J.; Hernández, F.; Ávila, J. GSK-3β, a Pivotal Kinase in Alzheimer Disease. Front. Mol. Neurosci., 2014, 7, 46.
71. Parkinson, J. An Essay on the Shaking Palsy. 1817. J. Neuropsychiatry Clin. Neurosci., 2002, 14 (2), 223-236; discussion 222.
72. Dauer, W.; Przedborski, S. Parkinson’s Disease: Mechanisms and Models. Neuron, 2003, 39 (6), 889-909.
73. Albin, R. L.; Young, A. B.; Penney, J. B. The Functional Anatomy of Basal Ganglia Disorders. Trends Neurosci., 1989, 12 (10), 366-375.
74. Lewy, F. H. Paralysis Agitans. I. Pathologische Anatomie. Handb. Neurol., 1912, 3 (part 2), 920-933.
75. Hassler, R. Zur Pathologie Der Paralysis Agitans Und Des Postenzephalitischen Parkinsonismus. J. Psychol. Neurol., 1938, 48, 387-476.
76. Cotzias, G. C.; Papavasiliou, P. S.; Gellene, R. L-Dopa in Parkinson’s Syndrome. N. Engl. J. Med., 1969, 281 (5), 272.
77. Schapira, A. H. V. Present and Future Drug Treatment for Parkinson’s Disease. J. Neurol. Neurosurg. Psychiatry, 2005, 76 (11), 1472-1478.
78. Constantinescu, R. Update on the Use of Pramipexole in the Treatment of Parkinson’s Disease. Neuropsychiatr. Dis. Treat., 2008, 4 (2), 337-352.
79. Alpha-Synuclein. Wikipedia, the free encyclopedia; 2015.
80. Ascherio, A.; Chen, H.; Weisskopf, M. G.; O’Reilly, E.; McCullough, M. L.; Calle, E. E.; Schwarzschild, M. A.; Thun, M. J. Pesticide Exposure and Risk for Parkinson’s Disease. Ann. Neurol., 2006, 60 (2), 197-203.
81. Priyadarshi, A.; Khuder, S. A.; Schaub, E. A.; Shrivastava, S. A Meta-Analysis of Parkinson’s Disease and Exposure to Pesticides. Neurotoxicology, 2000, 21 (4), 435-440.
82. Hatcher, J. M.; Pennell, K. D.; Miller, G. W. Parkinson’s Disease and Pesticides: A Toxicological Perspective. Trends Pharmacol. Sci., 2008, 29 (6), 322-329.
83. McCormack, A. L.; Thiruchelvam, M.; Manning-Bog, A. B.; Thiffault, C.; Langston, J. W.; Cory-Slechta, D. A.; Di Monte, D. A. Environmental Risk Factors and Parkinson’s Disease: Selective Degeneration of Nigral Dopaminergic Neurons Caused by the Herbicide Paraquat. Neurobiol. Dis., 2002, 10 (2), 119-127.
84. Manning-Bog, A. B.; McCormack, A. L.; Li, J.; Uversky, V. N.; Fink, A. L.; Di Monte, D. A. The Herbicide Paraquat Causes up-Regulation and Aggregation of Alpha-Synuclein in Mice: Paraquat and Alpha-Synuclein. J. Biol. Chem., 2002, 277 (3), 1641-1644.
85. Betarbet, R.; Sherer, T. B.; MacKenzie, G.; Garcia-Osuna, M.; Panov, A. V.; Greenamyre, J. T. Chronic Systemic Pesticide Exposure Reproduces Features of Parkinson’s Disease. Nat. Neurosci., 2000, 3 (12), 1301-1306.
86. Thomas, B.; Beal, M. F. Parkinson’s Disease. Hum. Mol. Genet., 2007, 16 Spec No. 2, R183-R194.
87. Souza, J. M.; Giasson, B. I.; Chen, Q.; Lee, V. M.; Ischiropoulos, H. Dityrosine Cross-Linking Promotes Formation of Stable Alpha -Synuclein Polymers. Implication of Nitrative and Oxidative Stress in the Pathogenesis of Neurodegenerative Synucleinopathies. J. Biol. Chem., 2000, 275 (24), 18344-18349.
88. Giasson, B. I.; Duda, J. E.; Murray, I. V.; Chen, Q.; Souza, J. M.; Hurtig, H. I.; Ischiropoulos, H.; Trojanowski, J. Q.; Lee, V. M. Oxidative Damage Linked to Neurodegeneration by Selective Alpha-Synuclein Nitration in Synucleinopathy Lesions. Science, 2000, 290 (5493), 985-989.
89. Yu, Z.; Xu, X.; Xiang, Z.; Zhou, J.; Zhang, Z.; Hu, C.; He, C. Nitrated Alpha-Synuclein Induces the Loss of Dopaminergic Neurons in the Substantia Nigra of Rats. PloS One, 2010, 5 (4), e9956.
90. Hooper, D. C.; Spitsin, S.; Kean, R. B.; Champion, J. M.; Dickson, G. M.; Chaudhry, I.; Koprowski, H. Uric Acid, a Natural Scavenger of Peroxynitrite, in Experimental Allergic Encephalomyelitis and Multiple Sclerosis. Proc. Natl. Acad. Sci. U. S. A., 1998, 95 (2), 675-680.
91. Alonso, A.; Rodríguez, L. A. G.; Logroscino, G.; Hernán, M. A. Gout and Risk of Parkinson Disease: A Prospective Study. Neurology, 2007, 69 (17), 1696-1700.
92. De Vera, M.; Rahman, M. M.; Rankin, J.; Kopec, J.; Gao, X.; Choi, H. Gout and the Risk of Parkinson’s Disease: A Cohort Study. Arthritis Rheum., 2008, 59 (11), 1549-1554.
93. Przedborski, S.; Jackson-Lewis, V.; Yokoyama, R.; Shibata, T.; Dawson, V. L.; Dawson, T. M. Role of Neuronal Nitric Oxide in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)-Induced Dopaminergic Neurotoxicity. Proc. Natl. Acad. Sci. U. S. A., 1996, 93 (10), 4565-4571.
94. Dehmer, T.; Lindenau, J.; Haid, S.; Dichgans, J.; Schulz, J. B. Deficiency of Inducible Nitric Oxide Synthase Protects against MPTP Toxicity in Vivo. J. Neurochem., 2000, 74 (5), 2213-2216.
95. Good, P. F.; Hsu, A.; Werner, P.; Perl, D. P.; Olanow, C. W. Protein Nitration in Parkinson’s Disease. J. Neuropathol. Exp. Neurol., 1998, 57 (4), 338-342.
96. Duda, J. E.; Lee, V. M.; Trojanowski, J. Q. Neuropathology of Synuclein Aggregates. J. Neurosci. Res., 2000, 61 (2), 121-127.
97. Hung, L. W.; Villemagne, V. L.; Cheng, L.; Sherratt, N. A.; Ayton, S.; White, A. R.; Crouch, P. J.; Lim, S.; Leong, S. L.; Wilkins, S.; George, J.; Roberts, B. R.; Pham, C. L. L.; Liu, X.; Chiu, F. C. K.; Shackleford, D. M.; Powell, A. K.; Masters, C. L.; Bush, A. I.; O’Keefe, G.; Culvenor, J. G.; Cappai, R.; Cherny, R. A.; Donnelly, P. S.; Hill, A. F.; Finkelstein, D. I.; Barnham, K. J. The Hypoxia Imaging Agent CuII(atsm) Is Neuroprotective and Improves Motor and Cognitive Functions in Multiple Animal Models of Parkinson’s Disease. J. Exp. Med., 2012, 209 (4), 837-854.
98. Charcot, J. M. Et A. Joffroy: Deux Cas D’atrophie Musculaire Progressive Avec Lésions de La Substance Grise et Des Faisceaux Antéro-Latéraux de La Moelle épinière. Arch Physiol Norm Path 2, (354), 629.
99. Cleveland, D. W.; Rothstein, J. D. From Charcot to Lou Gehrig: Deciphering Selective Motor Neuron Death in ALS. Nat. Rev. Neurosci., 2001, 2 (11), 806-819.
100. Talbot, K. Motor Neuron Disease: The Bare Essentials. Pract. Neurol., 2009, 9 (5), 303-309.
101. Davenport, R. J.; Swingler, R. J.; Chancellor, A. M.; Warlow, C. P. Avoiding False Positive Diagnoses of Motor Neuron Disease: Lessons from the Scottish Motor Neuron Disease Register. J. Neurol. Neurosurg. Psychiatry, 1996, 60 (2), 147-151.
102. Ferguson, T. A.; Elman, L. B. Clinical Presentation and Diagnosis of Amyotrophic Lateral Sclerosis. NeuroRehabilitation, 2007, 22 (6), 409-416.
103. Gordon, P. H.; Cheng, B.; Katz, I. B.; Pinto, M.; Hays, A. P.; Mitsumoto, H.; Rowland, L. P. The Natural History of Primary Lateral Sclerosis. Neurology, 2006, 66 (5), 647-653.
104. Duffy, J. R.; Peach, R. K.; Strand, E. A. Progressive Apraxia of Speech as a Sign of Motor Neuron Disease. Am. J. Speech-Lang. Pathol. Am. Speech-Lang.-Hear. Assoc., 2007, 16 (3), 198-208.
105. Stambler, N.; Charatan, M.; Cedarbaum, J. M. Prognostic Indicators of Survival in ALS. ALS CNTF Treatment Study Group. Neurol., 1998, 50 (1), 66-72.
106. Maruyama, H.; Morino, H.; Ito, H.; Izumi, Y.; Kato, H.; Watanabe, Y.; Kinoshita, Y.; Kamada, M.; Nodera, H.; Suzuki, H.; Komure, O.; Matsuura, S.; Kobatake, K.; Morimoto, N.; Abe, K.; Suzuki, N.; Aoki, M.; Kawata, A.; Hirai, T.; Kato, T.; Ogasawara, K.; Hirano, A.; Takumi, T.; Kusaka, H.; Hagiwara, K.; Kaji, R.; Kawakami, H. Mutations of Optineurin in Amyotrophic Lateral Sclerosis. Nature, 2010, 465 (7295), 223-226.
107. Beleza-Meireles, A.; Al-Chalabi, A. Genetic Studies of Amyotrophic Lateral Sclerosis: Controversies and Perspectives. Amyotroph. Lateral Scler. Off. Publ. World Fed. Neurol. Res. Group Mot. Neuron Dis., 2009, 10 (1), 1-14.
108. Kiernan, M. C.; Vucic, S.; Cheah, B. C.; Turner, M. R.; Eisen, A.; Hardiman, O.; Burrell, J. R.; Zoing, M. C. Amyotrophic Lateral Sclerosis. The Lancet, 2011, 377 (9769), 942-955.
109. 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. Amyotrophic Lateral Sclerosis and Structural Defects in Cu,Zn Superoxide Dismutase. Science, 1993, 261 (5124), 1047-1051.
110. McCord, J. M.; Fridovich, I. Superoxide Dismutase. An Enzymic Function for Erythrocuprein (hemocuprein). J. Biol. Chem., 1969, 244 (22), 6049-6055.
111. Kong, J.; Xu, Z. Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1. J. Neurosci. Off. J. Soc. Neurosci., 1998, 18 (9), 3241-3250.
112. Forman, H. J.; Fridovich, I. On the Stability of Bovine Superoxide Dismutase. The Effects of Metals. J. Biol. Chem., 1973, 248 (8), 2645-2649.
113. Bruijn, L. I.; Houseweart, M. K.; Kato, S.; Anderson, K. L.; Anderson, S. D.; Ohama, E.; Reaume, A. G.; Scott, R. W.; Cleveland, D. W. Aggregation and Motor Neuron Toxicity of an ALS-Linked SOD1 Mutant Independent from Wild-Type SOD1. Science, 1998, 281 (5384), 1851-1854.
114. Zetterström, P.; Stewart, H. G.; Bergemalm, D.; Jonsson, P. A.; Graffmo, K. S.; Andersen, P. M.; Brännström, T.; Oliveberg, M.; Marklund, S. L. Soluble Misfolded Subfractions of Mutant Superoxide Dismutase-1s Are Enriched in Spinal Cords throughout Life in Murine ALS Models. Proc. Natl. Acad. Sci. U. S. A., 2007, 104 (35), 14157-14162.
115. Gaudette, M.; Hirano, M.; Siddique, T. Current Status of SOD1 Mutations in Familial Amyotrophic Lateral Sclerosis. Amyotroph. Lateral Scler. Mot. Neuron Disord. Off. Publ. World Fed. Neurol. Res. Group Mot. Neuron Dis., 2000, 1 (2), 83-89.
116. Rosen, D. R. Mutations in Cu/Zn Superoxide Dismutase Gene Are Associated with Familial Amyotrophic Lateral Sclerosis. Nature, 1993, 364 (6435), 362.
117. Awano, T.; Johnson, G. S.; Wade, C. M.; Katz, M. L.; Johnson, G. C.; Taylor, J. F.; Perloski, M.; Biagi, T.; Baranowska, I.; Long, S.; March, P. A.; Olby, N. J.; Shelton, G. D.; Khan, S.; O’Brien, D. P.; Lindblad-Toh, K.; Coates, J. R. Genome-Wide Association Analysis Reveals a SOD1 Mutation in Canine Degenerative Myelopathy That Resembles Amyotrophic Lateral Sclerosis. Proc. Natl. Acad. Sci. U. S. A., 2009, 106 (8), 2794-2799.
118. Crow, J. P.; Sampson, J. B.; Zhuang, Y.; Thompson, J. A.; Beckman, J. S. Decreased Zinc Affinity of Amyotrophic Lateral Sclerosis-Associated Superoxide Dismutase Mutants Leads to Enhanced Catalysis of Tyrosine Nitration by Peroxynitrite. J. Neurochem., 1997, 69 (5), 1936-1944.
119. Crow, J. P.; Ye, Y. Z.; Strong, M.; Kirk, M.; Barnes, S.; Beckman, J. S. Superoxide Dismutase Catalyzes Nitration of Tyrosines by Peroxynitrite in the Rod and Head Domains of Neurofilament-L. J. Neurochem., 1997, 69 (5), 1945-1953.
120. Beckman, J. S.; Carson, M.; Smith, C. D.; Koppenol, W. H. ALS, SOD and Peroxynitrite. Nature, 1993, 364 (6438), 584.
121. Beal, M. F.; Ferrante, R. J.; Browne, S. E.; Matthews, R. T.; Kowall, N. W.; Brown, R. H. Increased 3-Nitrotyrosine in Both Sporadic and Familial Amyotrophic Lateral Sclerosis. Ann. Neurol., 1997, 42 (4), 644-654.
122. Basso, M.; Samengo, G.; Nardo, G.; Massignan, T.; D’Alessandro, G.; Tartari, S.; Cantoni, L.; Marino, M.; Cheroni, C.; De Biasi, S.; Giordana, M. T.; Strong, M. J.; Estevez, A. G.; Salmona, M.; Bendotti, C.; Bonetto, V. Characterization of Detergent-Insoluble Proteins in ALS Indicates a Causal Link between Nitrative Stress and Aggregation in Pathogenesis. PloS One, 2009, 4 (12), e8130.
123. Casoni, F.; Basso, M.; Massignan, T.; Gianazza, E.; Cheroni, C.; Salmona, M.; Bendotti, C.; Bonetto, V. Protein Nitration in a Mouse Model of Familial Amyotrophic Lateral Sclerosis: Possible Multifunctional Role in the Pathogenesis. J. Biol. Chem., 2005, 280 (16), 16295-16304.
124. Corrado, L.; Ratti, A.; Gellera, C.; Buratti, E.; Castellotti, B.; Carlomagno, Y.; Ticozzi, N.; Mazzini, L.; Testa, L.; Taroni, F.; Baralle, F. E.; Silani, V.; D’Alfonso, S. High Frequency of TARDBP Gene Mutations in Italian Patients with Amyotrophic Lateral Sclerosis. Hum. Mutat., 2009, 30 (4), 688-694.
125. Daoud, H.; Valdmanis, P. N.; Kabashi, E.; Dion, P.; Dupré, N.; Camu, W.; Meininger, V.; Rouleau, G. A. Contribution of TARDBP Mutations to Sporadic Amyotrophic Lateral Sclerosis. J. Med. Genet., 2009, 46 (2), 112-114.
126. Gitcho, M. A.; Baloh, R. H.; Chakraverty, S.; Mayo, K.; Norton, J. B.; Levitch, D.; Hatanpaa, K. J.; White, C. L.; Bigio, E. H.; Caselli, R.; Baker, M.; Al-Lozi, M. T.; Morris, J. C.; Pestronk, A.; Rademakers, R.; Goate, A. M.; Cairns, N. J. TDP-43 A315T Mutation in Familial Motor Neuron Disease. Ann. Neurol., 2008, 63 (4), 535-538.
127. Kabashi, E.; Valdmanis, P. N.; Dion, P.; Spiegelman, D.; McConkey, B. J.; Vande Velde, C.; Bouchard, J.-P.; Lacomblez, L.; Pochigaeva, K.; Salachas, F.; Pradat, P.-F.; Camu, W.; Meininger, V.; Dupre, N.; Rouleau, G. A. TARDBP Mutations in Individuals with Sporadic and Familial Amyotrophic Lateral Sclerosis. Nat. Genet., 2008, 40 (5), 572-574.
128. Sreedharan, J.; Blair, I. P.; Tripathi, V. B.; Hu, X.; Vance, C.; Rogelj, B.; Ackerley, S.; Durnall, J. C.; Williams, K. L.; Buratti, E.; Baralle, F.; de Belleroche, J.; Mitchell, J. D.; Leigh, P. N.; Al-Chalabi, A.; Miller, C. C.; Nicholson, G.; Shaw, C. E. TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis. Science, 2008, 319 (5870), 1668-1672.
129. Van Deerlin, V. M.; Leverenz, J. B.; Bekris, L. M.; Bird, T. D.; Yuan, W.; Elman, L. B.; Clay, D.; Wood, E. M.; Chen-Plotkin, A. S.; Martinez-Lage, M.; Steinbart, E.; McCluskey, L.; Grossman, M.; Neumann, M.; Wu, I.-L.; Yang, W.-S.; Kalb, R.; Galasko, D. R.; Montine, T. J.; Trojanowski, J. Q.; Lee, V. M.-Y.; Schellenberg, G. D.; Yu, C.-E. TARDBP Mutations in Amyotrophic Lateral Sclerosis with TDP-43 Neuropathology: A Genetic and Histopathological Analysis. Lancet Neurol., 2008, 7 (5), 409-416.
130. Ou, S. H.; Wu, F.; Harrich, D.; García-Martínez, L. F.; Gaynor, R. B. Cloning and Characterization of a Novel Cellular Protein, TDP-43, That Binds to Human Immunodeficiency Virus Type 1 TAR DNA Sequence Motifs. J. Virol., 1995, 69 (6), 3584-3596.
131. Winton, M. J.; Igaz, L. M.; Wong, M. M.; Kwong, L. K.; Trojanowski, J. Q.; Lee, V. M.-Y. Disturbance of Nuclear and Cytoplasmic TAR DNA-Binding Protein (TDP-43) Induces Disease-like Redistribution, Sequestration, and Aggregate Formation. J. Biol. Chem., 2008, 283 (19), 13302-13309.
132. Gregory, R. I.; Yan, K.-P.; Amuthan, G.; Chendrimada, T.; Doratotaj, B.; Cooch, N.; Shiekhattar, R. The Microprocessor Complex Mediates the Genesis of microRNAs. Nature, 2004, 432 (7014), 235-240.
133. Xu, Z.-S. Does a Loss of TDP-43 Function Cause Neurodegeneration? Mol. Neurodegener., 2012, 7, 27.
134. Ayala, Y. M.; De Conti, L.; Avendaño-Vázquez, S. E.; Dhir, A.; Romano, M.; D’Ambrogio, A.; Tollervey, J.; Ule, J.; Baralle, M.; Buratti, E.; Baralle, F. E. TDP-43 Regulates Its mRNA Levels through a Negative Feedback Loop. EMBO J., 2011, 30 (2), 277-288.
135. Polymenidou, M.; Lagier-Tourenne, C.; Hutt, K. R.; Huelga, S. C.; Moran, J.; Liang, T. Y.; Ling, S.-C.; Sun, E.; Wancewicz, E.; Mazur, C.; Kordasiewicz, H.; Sedaghat, Y.; Donohue, J. P.; Shiue, L.; Bennett, C. F.; Yeo, G. W.; Cleveland, D. W. Long Pre-mRNA Depletion and RNA Missplicing Contribute to Neuronal Vulnerability from Loss of TDP-43. Nat. Neurosci., 2011, 14 (4), 459-468.
136. Tollervey, J. R.; Curk, T.; Rogelj, B.; Briese, M.; Cereda, M.; Kayikci, M.; König, J.; Hortobágyi, T.; Nishimura, A. L.; Zupunski, V.; Patani, R.; Chandran, S.; Rot, G.; Zupan, B.; Shaw, C. E.; Ule, J. Characterizing the RNA Targets and Position-Dependent Splicing Regulation by TDP-43. Nat. Neurosci., 2011, 14 (4), 452-458.
137. Carlomagno, Y.; Zhang, Y.; Davis, M.; Lin, W.-L.; Cook, C.; Dunmore, J.; Tay, W.; Menkosky, K.; Cao, X.; Petrucelli, L.; Deture, M. Casein Kinase II Induced Polymerization of Soluble TDP-43 into Filaments Is Inhibited by Heat Shock Proteins. PloS One, 2014, 9 (3), e90452.
138. Al-Sarraj, S.; King, A.; Troakes, C.; Smith, B.; Maekawa, S.; Bodi, I.; Rogelj, B.; Al-Chalabi, A.; Hortobágyi, T.; Shaw, C. E. p62 Positive, TDP-43 Negative, Neuronal Cytoplasmic and Intranuclear Inclusions in the Cerebellum and Hippocampus Define the Pathology of C9orf72-Linked FTLD and MND/ALS. Acta Neuropathol. (Berl.), 2011, 122 (6), 691-702.
139. Bose, J. K.; Huang, C.-C.; Shen, C.-K. J. Regulation of Autophagy by Neuropathological Protein TDP-43. J. Biol. Chem., 2011, 286 (52), 44441-44448.
140. Barmada, S. J.; Skibinski, G.; Korb, E.; Rao, E. J.; Wu, J. Y.; Finkbeiner, S. Cytoplasmic Mislocalization of TDP-43 Is Toxic to Neurons and Enhanced by a Mutation Associated with Familial Amyotrophic Lateral Sclerosis. J. Neurosci. Off. J. Soc. Neurosci., 2010, 30 (2), 639-649.
141. Diaper, D. C.; Adachi, Y.; Sutcliffe, B.; Humphrey, D. M.; Elliott, C. J. H.; Stepto, A.; Ludlow, Z. N.; Vanden Broeck, L.; Callaerts, P.; Dermaut, B.; Al-Chalabi, A.; Shaw, C. E.; Robinson, I. M.; Hirth, F. Loss and Gain of Drosophila TDP-43 Impair Synaptic Efficacy and Motor Control Leading to Age-Related Neurodegeneration by Loss-of-Function Phenotypes. Hum. Mol. Genet., 2013, 22 (8), 1539-1557.
142. Arai, T.; Hasegawa, M.; Akiyama, H.; Ikeda, K.; Nonaka, T.; Mori, H.; Mann, D.; Tsuchiya, K.; Yoshida, M.; Hashizume, Y.; Oda, T. TDP-43 Is a Component of Ubiquitin-Positive Tau-Negative Inclusions in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Biochem. Biophys. Res. Commun., 2006, 351 (3), 602-611.
143. Neumann, M.; Sampathu, D. M.; Kwong, L. K.; Truax, A. C.; Micsenyi, M. C.; Chou, T. T.; Bruce, J.; Schuck, T.; Grossman, M.; Clark, C. M.; McCluskey, L. F.; Miller, B. L.; Masliah, E.; Mackenzie, I. R.; Feldman, H.; Feiden, W.; Kretzschmar, H. A.; Trojanowski, J. Q.; Lee, V. M.-Y. Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science, 2006, 314 (5796), 130-133.
144. Ringholz, G. M.; Appel, S. H.; Bradshaw, M.; Cooke, N. A.; Mosnik, D. M.; Schulz, P. E. Prevalence and Patterns of Cognitive Impairment in Sporadic ALS. Neurology, 2005, 65 (4), 586-590.
145. Miller, R. G.; Mitchell, J. D.; Moore, D. H. Riluzole for Amyotrophic Lateral Sclerosis (ALS)/motor Neuron Disease (MND). Cochrane Database Syst. Rev., 2012, 3, CD001447.
146. Bellingham, M. C. A Review of the Neural Mechanisms of Action and Clinical Efficiency of Riluzole in Treating Amyotrophic Lateral Sclerosis: What Have We Learned in the Last Decade? CNS Neurosci. Ther., 2011, 17 (1), 4-31.
147. Traynor, B. J.; Alexander, M.; Corr, B.; Frost, E.; Hardiman, O. An Outcome Study of Riluzole in Amyotrophic Lateral Sclerosis--a Population-Based Study in Ireland, 1996-2000. J. Neurol., 2003, 250 (4), 473-479.
148. Van den Berg, J. P.; Kalmijn, S.; Lindeman, E.; Veldink, J. H.; de Visser, M.; Van der Graaff, M. M.; Wokke, J. H. J.; Van den Berg, L. H. Multidisciplinary ALS Care Improves Quality of Life in Patients with ALS. Neurology, 2005, 65 (8), 1264-1267.
149. Soon, C. P. W.; Donnelly, P. S.; Turner, B. J.; Hung, L. W.; Crouch, P. J.; Sherratt, N. A.; Tan, J.-L.; Lim, N. K.-H.; Lam, L.; Bica, L.; Lim, S.; Hickey, J. L.; Morizzi, J.; Powell, A.; Finkelstein, D. I.; Culvenor, J. G.; Masters, C. L.; Duce, J.; White, A. R.; Barnham, K. J.; Li, Q.-X. Diacetylbis(N(4)-Methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-Induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model. J. Biol. Chem., 2011, 286 (51), 44035-44044.
150. McAllum, E. J.; Lim, N. K.-H.; Hickey, J. L.; Paterson, B. M.; Donnelly, P. S.; Li, Q.-X.; Liddell, J. R.; Barnham, K. J.; White, A. R.; Crouch, P. J. Therapeutic Effects of CuII(atsm) in the SOD1-G37R Mouse Model of Amyotrophic Lateral Sclerosis. Amyotroph. Lateral Scler. Front. Degener., 2013, 14 (7-8), 586-590.
151. Roberts, B. R.; Lim, N. K. H.; McAllum, E. J.; Donnelly, P. S.; Hare, D. J.; Doble, P. A.; Turner, B. J.; Price, K. A.; Lim, S. C.; Paterson, B. M.; Hickey, J. L.; Rhoads, T. W.; Williams, J. R.; Kanninen, K. M.; Hung, L. W.; Liddell, J. R.; Grubman, A.; Monty, J.-F.; Llanos, R. M.; Kramer, D. R.; Mercer, J. F. B.; Bush, A. I.; Masters, C. L.; Duce, J. A.; Li, Q.-X.; Beckman, J. S.; Barnham, K. J.; White, A. R.; Crouch, P. J. Oral Treatment with CuII(atsm) Increases Mutant SOD1 In Vivo but Protects Motor Neurons and Improves the Phenotype of a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. J. Neurosci., 2014, 34 (23), 8021-8031.