{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T14:42:21Z","timestamp":1778337741229,"version":"3.51.4"},"reference-count":103,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T00:00:00Z","timestamp":1604448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001782","name":"University of Melbourne","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001782","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014012","name":"FightMND","doi-asserted-by":"publisher","award":["04_TRG_2017_Crouch"],"award-info":[{"award-number":["04_TRG_2017_Crouch"]}],"id":[{"id":"10.13039\/100014012","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014331","name":"Motor Neurone Disease Australia","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100014331","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>The blood\u2013brain barrier permeant, copper-containing compound, CuII(atsm), has successfully progressed from fundamental research outcomes in the laboratory through to phase 2\/3 clinical assessment in patients with the highly aggressive and fatal neurodegenerative condition of amyotrophic lateral sclerosis (ALS). The most compelling outcomes to date to indicate potential for disease-modification have come from pre-clinical studies utilising mouse models that involve transgenic expression of mutated superoxide dismutase 1 (SOD1). Mutant SOD1 mice provide a very robust mammalian model of ALS with high validity, but mutations in SOD1 account for only a small percentage of ALS cases in the clinic, with the preponderant amount of cases being sporadic and of unknown aetiology. As per other putative drugs for ALS developed and tested primarily in mutant SOD1 mice, this raises important questions about the pertinence of CuII(atsm) to broader clinical translation. This review highlights some of the challenges associated with the clinical translation of new treatment options for ALS. It then provides a brief account of pre-clinical outcomes for CuII(atsm) in SOD1 mouse models of ALS, followed by an outline of additional studies which report positive outcomes for CuII(atsm) when assessed in cell and mouse models of neurodegeneration which do not involve mutant SOD1. Clinical evidence for CuII(atsm) selectively targeting affected regions of the CNS in patients is also presented. Overall, this review summarises the existing evidence which indicates why clinical relevance of CuII(atsm) likely extends beyond the context of cases of ALS caused by mutant SOD1.<\/jats:p>","DOI":"10.3390\/life10110271","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T10:32:36Z","timestamp":1604485956000},"page":"271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Copper-ATSM as a Treatment for ALS: Support from Mutant SOD1 Models and Beyond"],"prefix":"10.3390","volume":"10","author":[{"given":"Sara","family":"Nikseresht","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James B.W.","family":"Hilton","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-2850","authenticated-orcid":false,"given":"Kai","family":"Kysenius","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics and Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0798-5338","authenticated-orcid":false,"given":"Jeffrey R.","family":"Liddell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7777-4747","authenticated-orcid":false,"given":"Peter J.","family":"Crouch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics and Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S0140-6736(10)61156-7","article-title":"Amyotrophic lateral sclerosis","volume":"377","author":"Kiernan","year":"2011","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1097\/WCO.0000000000000730","article-title":"Epidemiology of amyotrophic lateral sclerosis: An update of recent literature","volume":"32","author":"Longinetti","year":"2019","journal-title":"Curr. Opin. Neurol."},{"key":"ref_3","unstructured":"National Institute for Clinical Excellence (2019). Motor Neurone Disease: Assessment and Management, National Institute for Clinical Excellence."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3551","DOI":"10.2174\/0929867321666140916120118","article-title":"The glutamate hypothesis in ALS: Pathophysiology and drug development","volume":"21","author":"Blasco","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1080\/21678421.2017.1369125","article-title":"July 2017 ENCALS statement on edaravone","volume":"18","author":"Andersen","year":"2017","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/med.21528","article-title":"Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs","volume":"39","author":"Jaiswal","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/21678421.2019.1632346","article-title":"Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: A randomized clinical trial","volume":"21","author":"Mora","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_8","first-page":"1261","article-title":"JETALS: The Japanese Early-stage Trial of high dose methylcobalamin for ALS","volume":"71","author":"Izumi","year":"2019","journal-title":"Brain Nerve"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fnins.2020.00195","article-title":"Intramuscular Injection of Bone Marrow Stem Cells in Amyotrophic Lateral Sclerosis Patients: A Randomized Clinical Trial","volume":"14","author":"Blanquer","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104793","DOI":"10.1016\/j.nbd.2020.104793","article-title":"Gene therapy for overexpressing Neuregulin 1 type I in skeletal muscles promotes functional improvement in the SOD1(G93A) ALS mice","volume":"137","author":"Solanes","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jbior.2015.10.006","article-title":"SOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALS","volume":"60","author":"Hayashi","year":"2016","journal-title":"Adv. Biol. Regul."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/362059a0","article-title":"Mutations in Cu\/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis","volume":"362","author":"Rosen","year":"1993","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/S1474-4422(13)70061-9","article-title":"An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: A phase 1, randomised, first-in-man study","volume":"12","author":"Miller","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1172\/JCI25424","article-title":"Antisense oligonucleotide therapy for neurodegenerative disease","volume":"116","author":"Smith","year":"2006","journal-title":"J. Clin. Invest."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.neuron.2013.10.015","article-title":"RNA toxicity from the ALS\/FTD C9ORF72 expansion is mitigated by antisense intervention","volume":"80","author":"Donnelly","year":"2013","journal-title":"Neuron"},{"key":"ref_16","first-page":"E4530","article-title":"Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration","volume":"110","author":"Baughn","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cappella, M., Ciotti, C., Cohen-Tannoudji, M., and Biferi, M.G. (2019). Gene Therapy for ALS-A Perspective. Int. J. Mol. Sci, 20.","DOI":"10.3390\/ijms20184388"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/nature09320","article-title":"Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS","volume":"466","author":"Elden","year":"2010","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"532","DOI":"10.3389\/fnins.2019.00532","article-title":"Motor Neuron Susceptibility in ALS\/FTD","volume":"13","author":"Ragagnin","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1126\/science.1154584","article-title":"TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis","volume":"319","author":"Sreedharan","year":"2008","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.1165942","article-title":"Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6","volume":"323","author":"Vance","year":"2009","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1093\/brain\/awx370","article-title":"Hot-spot KIF5A mutations cause familial ALS","volume":"141","author":"Brenner","year":"2018","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S1474-4422(17)30401-5","article-title":"Novel genes associated with amyotrophic lateral sclerosis: Diagnostic and clinical implications","volume":"17","author":"Chia","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1126\/science.8209258","article-title":"Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation","volume":"264","author":"Gurney","year":"1994","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1073\/pnas.92.3.689","article-title":"Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis","volume":"92","author":"Ripps","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bonifacino, T., Rebosio, C., Provenzano, F., Torazza, C., Balbi, M., Milanese, M., Raiteri, L., Usai, C., Fedele, E., and Bonanno, G. (2019). Enhanced Function and Overexpression of Metabotropic Glutamate Receptors 1 and 5 in the Spinal Cord of the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis during Disease Progression. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184552"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jneuroim.2014.03.005","article-title":"Endoplasmic reticulum stress is accompanied by activation of NF-kappaB in amyotrophic lateral sclerosis","volume":"270","author":"Prell","year":"2014","journal-title":"J. Neuroimmunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1523\/JNEUROSCI.18-09-03241.1998","article-title":"Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1","volume":"18","author":"Kong","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.nbd.2006.01.001","article-title":"Bioenergetic abnormalities in discrete cerebral motor pathways presage spinal cord pathology in the G93A SOD1 mouse model of ALS","volume":"22","author":"Browne","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s41419-019-1451-2","article-title":"Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1(G93A) Model","volume":"10","author":"Ionescu","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1093\/hmg\/10.19.2013","article-title":"Oxidative stress causes abnormal accumulation of familial amyotrophic lateral sclerosis-related mutant SOD1 in transgenic Caenorhabditis elegans","volume":"10","author":"Oeda","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.cmet.2008.09.002","article-title":"Skeletal muscle is a primary target of SOD1G93A-mediated toxicity","volume":"8","author":"Dobrowolny","year":"2008","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e36892","DOI":"10.7554\/eLife.36892","article-title":"Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9","volume":"7","author":"Commisso","year":"2018","journal-title":"eLife"},{"key":"ref_35","first-page":"348765","article-title":"Genetic rodent models of amyotrophic lateral sclerosis","volume":"2011","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/0896-6273(95)90259-7","article-title":"An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria","volume":"14","author":"Wong","year":"1995","journal-title":"Neuron"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.drudis.2007.10.011","article-title":"Strategic approaches to developing drug treatments for ALS","volume":"13","author":"Vincent","year":"2008","journal-title":"Drug Discov. Today"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fnagi.2017.00068","article-title":"ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?","volume":"9","author":"Petrov","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1159\/000089620","article-title":"Excitotoxicity and amyotrophic lateral sclerosis","volume":"2","author":"Dewil","year":"2005","journal-title":"Neurodegener Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3988\/jcn.2007.3.4.181","article-title":"Oral administration of memantine prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis","volume":"3","author":"Joo","year":"2007","journal-title":"J. Clin. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S1474-4422(14)70222-4","article-title":"Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: A multi-stage, randomised, double-blind, placebo-controlled trial","volume":"13","author":"Cudkowicz","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3109\/17482968.2010.498521","article-title":"A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis","volume":"11","author":"Pinto","year":"2010","journal-title":"Amyotroph Lateral Scler."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/978-981-13-8367-0_5","article-title":"Crosstalk Between Oxidative Stress and Mitochondrial Damage: Focus on Amyotrophic Lateral Sclerosis","volume":"1158","author":"Greco","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.expneurol.2008.07.017","article-title":"Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice","volume":"213","author":"Ito","year":"2008","journal-title":"Exp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/6568","article-title":"Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis","volume":"5","author":"Klivenyi","year":"1999","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8892","DOI":"10.1073\/pnas.95.15.8892","article-title":"Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects","volume":"95","author":"Matthews","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/mus.25048","article-title":"Statins accelerate disease progression and shorten survival in SOD1(G93A) mice","volume":"54","author":"Su","year":"2016","journal-title":"Muscle Nerve"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/ana.21743","article-title":"Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III","volume":"66","author":"Kaufmann","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1212\/01.WNL.0000142992.81995.F0","article-title":"A clinical trial of creatine in ALS","volume":"63","author":"Shefner","year":"2004","journal-title":"Neurology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S1474-4422(17)30115-1","article-title":"Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: A randomised, double-blind, placebo-controlled trial","volume":"16","author":"Abe","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1080\/21678421.2017.1361442","article-title":"Post-hoc analysis of MCI186-17, the extension study to MCI186-16, the confirmatory double-blind, parallel-group, placebo-controlled study of edaravone in amyotrophic lateral sclerosis","volume":"18","author":"Takahashi","year":"2017","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3109\/17482960903545334","article-title":"Guidelines for preclinical animal research in ALS\/MND: A consensus meeting","volume":"11","author":"Ludolph","year":"2010","journal-title":"Amyotroph Lateral Scler."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/507423a","article-title":"Preclinical research: Make mouse studies work","volume":"507","author":"Perrin","year":"2014","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1080\/17482960701856300","article-title":"Design, power, and interpretation of studies in the standard murine model of ALS","volume":"9","author":"Scott","year":"2008","journal-title":"Amyotroph Lateral Scler."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ibror.2017.03.001","article-title":"CuATSM efficacy is independently replicated in a SOD1 mouse model of ALS while unmetallated ATSM therapy fails to reveal benefits","volume":"2","author":"Vieira","year":"2017","journal-title":"IBRO Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"44035","DOI":"10.1074\/jbc.M111.274407","article-title":"Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model","volume":"286","author":"Soon","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1248\/bpb.17.701","article-title":"Cu-ATSM, an intracellular-accessible superoxide dismutase (SOD)-like copper complex: Evaluation in an ischemia-reperfusion injury model","volume":"17","author":"Wada","year":"1994","journal-title":"Biol. Pharm. Bull."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2016.01.020","article-title":"Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD mice co-expressing the Copper-Chaperone-for-SOD","volume":"89","author":"Williams","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"8021","DOI":"10.1523\/JNEUROSCI.4196-13.2014","article-title":"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","volume":"34","author":"Roberts","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"42292","DOI":"10.1038\/srep42292","article-title":"CuII(atsm) improves the neurological phenotype and survival of SOD1G93A mice and selectively increases enzymatically active SOD1 in the spinal cord","volume":"7","author":"Hilton","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"586","DOI":"10.3109\/21678421.2013.824000","article-title":"Therapeutic effects of CuII(atsm) in the SOD1G37R mouse model of amyotrophic lateral sclerosis","volume":"14","author":"McAllum","year":"2013","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6072","DOI":"10.1073\/pnas.0610923104","article-title":"Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology","volume":"104","author":"Son","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00109-015-1273-3","article-title":"Metal-deficient SOD1 in amyotrophic lateral sclerosis","volume":"93","author":"Hilton","year":"2015","journal-title":"J. Mol. Med. (Berl)"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Trist, B., Hilton, J.B., Crouch, P.J., Hare, D.J., and Double, K.L. Superoxide dismutase 1 in health and disease: How a front-line antioxidant becomes neurotoxic. Angew. Chem. Int. Ed. Engl., 2020.","DOI":"10.1002\/anie.202000451"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1016\/S0021-9258(19)44055-6","article-title":"On the stability of bovine superoxide dismutase. The effects of metals","volume":"248","author":"Forman","year":"1973","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.nbd.2013.01.001","article-title":"Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities","volume":"54","author":"Tokuda","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Tokuda, E., and Furukawa, Y. (2016). Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050636"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/j.1471-4159.2009.06310.x","article-title":"Dysregulation of intracellular copper trafficking pathway in a mouse model of mutant copper\/zinc superoxide dismutase-linked familial amyotrophic lateral sclerosis","volume":"111","author":"Tokuda","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.expneurol.2008.05.011","article-title":"Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis","volume":"213","author":"Tokuda","year":"2008","journal-title":"Exp. Neurol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.expneurol.2018.06.006","article-title":"The accumulation of enzymatically inactive cuproenzymes is a CNS-specific phenomenon of the SOD1(G37R) mouse model of ALS and can be restored by overexpressing the human copper transporter hCTR1","volume":"307","author":"Hilton","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1039\/C6MT00099A","article-title":"Endogenous Cu in the central nervous system fails to satiate the elevated requirement for Cu in a mutant SOD1 mouse model of ALS","volume":"8","author":"Hilton","year":"2016","journal-title":"Metallomics"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"15923","DOI":"10.1074\/jbc.M112087200","article-title":"Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis","volume":"277","author":"Hayward","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1111\/j.1471-4159.2007.04604.x","article-title":"The lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis","volume":"102","author":"Petri","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1016\/j.bbadis.2018.03.015","article-title":"A copper-deficient form of mutant Cu\/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis","volume":"1864","author":"Tokuda","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis. Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"14157","DOI":"10.1073\/pnas.0700477104","article-title":"Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models","volume":"104","author":"Zetterstrom","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1093\/brain\/awh704","article-title":"Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models","volume":"129","author":"Jonsson","year":"2006","journal-title":"Brain"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1126\/science.1134108","article-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"314","author":"Neumann","year":"2006","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1750-1326-6-57","article-title":"C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress","volume":"6","author":"Meyerowitz","year":"2011","journal-title":"Mol. Neurodegener"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.neuint.2012.01.019","article-title":"Endogenous TDP-43 localized to stress granules can subsequently form protein aggregates","volume":"60","author":"Parker","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Parker, S.J., Meyerowitz, J., James, J.L., Liddell, J.R., Nonaka, T., Hasegawa, M., Kanninen, K.M., Lim, S., Paterson, B.M., and Donnelly, P.S. (2012). Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042277"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Bica, L., Liddell, J.R., Donnelly, P.S., Duncan, C., Caragounis, A., Volitakis, I., Paterson, B.M., Cappai, R., Grubman, A., and Camakaris, J. (2014). Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090070"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1111\/bph.14881","article-title":"CuII(atsm) inhibits ferroptosis: Implications for treatment of neurodegenerative disease","volume":"177","author":"Southon","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.freeradbiomed.2018.09.033","article-title":"Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration","volume":"133","author":"Masaldan","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"104495","DOI":"10.1016\/j.nbd.2019.104495","article-title":"Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model","volume":"130","author":"Kuo","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6021","DOI":"10.1523\/JNEUROSCI.20-16-06021.2000","article-title":"Neuropathology in mice expressing human alpha-synuclein","volume":"20","author":"Wiederhold","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1515\/REVNEURO.2007.18.2.115","article-title":"Transgenic mice with human mutant genes causing Parkinson's disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration","volume":"18","author":"Martin","year":"2007","journal-title":"Rev. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1084\/jem.20112285","article-title":"The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease","volume":"209","author":"Hung","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"22398","DOI":"10.1038\/srep22398","article-title":"Gene dysregulation is restored in the Parkinson\u2019s disease MPTP neurotoxic mice model upon treatment of the therapeutic drug Cu(II)(atsm)","volume":"6","author":"Cheng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s13311-016-0504-9","article-title":"The copper bis(thiosemicarbazone) complex CuII(atsm) is protective against cerebral ischemia through modulation of the inflammatory milieu","volume":"14","author":"Huuskonen","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"668","DOI":"10.3389\/fnins.2018.00668","article-title":"CuII(atsm) attenuates neuroinflammation","volume":"12","author":"Choo","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_91","first-page":"1155","article-title":"Copper-62-ATSM: A new hypoxia imaging agent with high membrane permeability and low redox potential","volume":"38","author":"Fujibayashi","year":"1997","journal-title":"J. Nucl. Med."},{"key":"ref_92","first-page":"193","article-title":"Assessing tumor hypoxia by positron emission tomography with Cu-ATSM","volume":"53","author":"Holland","year":"2009","journal-title":"Q J. Nucl. Med. Mol. Imaging."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.nucmedbio.2011.08.008","article-title":"Radiolabeled Cu-ATSM as a novel indicator of overreduced intracellular state due to mitochondrial dysfunction: Studies with mitochondrial DNA-less rho(0) cells and cybrids carrying MELAS mitochondrial DNA mutation","volume":"39","author":"Yoshii","year":"2012","journal-title":"Nucl. Med. Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1073\/pnas.1116227108","article-title":"An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper","volume":"109","author":"Donnelly","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1517\/14728221003652489","article-title":"Targeting mitochondrial dysfunction in neurodegenerative disease: Part I","volume":"14","author":"Burchell","year":"2010","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1517\/14728221003730434","article-title":"Targeting mitochondrial dysfunction in neurodegenerative disease: Part II","volume":"14","author":"Burchell","year":"2010","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1212\/WNL.0000000000001588","article-title":"Increased oxidative stress is related to disease severity in the ALS motor cortex: A PET study","volume":"84","author":"Ikawa","year":"2015","journal-title":"Neurology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.nucmedbio.2011.02.016","article-title":"Evaluation of striatal oxidative stress in patients with Parkinson\u2019s disease using [62Cu]ATSM PET","volume":"38","author":"Ikawa","year":"2011","journal-title":"Nucl. Med. Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.mito.2009.01.011","article-title":"PET imaging of redox and energy states in stroke-like episodes of MELAS","volume":"9","author":"Ikawa","year":"2009","journal-title":"Mitochondrion"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Hilton, J.B.W., Kysenius, K., Liddell, J.R., Rautengarten, C., Mercer, S.W., Paul, B., Beckman, J.S., McLean, C., White, A.R., and Donnelly, P.S. (2020). Disrupted copper availability in sporadic ALS: Implications for CuII(atsm) as a treatment option. BioRxiv.","DOI":"10.1101\/2020.04.17.047704"},{"key":"ref_101","unstructured":"(2020, October 30). NCT02870634. ClinicalTrials.org Study # NCT02870634 \u201cPhase 1 Dose Escalation and PK Study of Cu(II)ATSM in ALS\/MND\u201d, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02870634."},{"key":"ref_102","unstructured":"(2020, October 30). NCT04082832. ClinicalTrials.org study # NCT04082832 \u201cCuATSM compared with placebo for treatment of ALS\/MND\u201d, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04082832."},{"key":"ref_103","unstructured":"(2020, October 30). NCT03204929. ClinicalTrials.org study # NCT03204929 \u201cDose Escalation Study of Cu(II)ATSM in Parkinson\u2019s Disease\u201d, Available online: https:\/\/clinicaltrials.gov\/show\/NCT03204929."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/10\/11\/271\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:29:13Z","timestamp":1760178553000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/10\/11\/271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,4]]},"references-count":103,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["life10110271"],"URL":"https:\/\/doi.org\/10.3390\/life10110271","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,4]]}}}