title: Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD.
abstract: Over-expression of mutant copper, zinc superoxide dismutase (SOD) in mice induces ALS and has become the most widely used model of neurodegeneration. However, no pharmaceutical agent in 20 years has extended lifespan by more than a few weeks. The Copper-Chaperone-for-SOD (CCS) protein completes the maturation of SOD by inserting copper, but paradoxically human CCS causes mice co-expressing mutant SOD to die within two weeks of birth. Hypothesizing that co-expression of CCS created copper deficiency in spinal cord, we treated these pups with the PET-imaging agent CuATSM, which is known to deliver copper into the CNS within minutes. CuATSM prevented the early mortality of CCSxSOD mice, while markedly increasing Cu, Zn SOD protein in their ventral spinal cord. Remarkably, continued treatment with CuATSM extended the survival of these mice by an average of 18 months. When CuATSM treatment was stopped, these mice developed ALS-related symptoms and died within 3 months. Restoring CuATSM treatment could rescue these mice after they became symptomatic, providing a means to start and stop disease progression. All ALS patients also express human CCS, raising the hope that familial SOD ALS patients could respond to CuATSM treatment similarly to the CCSxSOD mice.
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States.
authors.forename: Jared R
authors.initials: JR
authors.lastname: Williams
authors.affiliation: Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay; Institut Pasteur de Montevideo, Uruguay.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Trias
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Beilby
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States.
authors.forename: Nathan I
authors.initials: NI
authors.lastname: Lopez
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Labut
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States.
authors.forename: C Samuel
authors.initials: CS
authors.lastname: Bradford
authors.affiliation: Florey Institute, University of Melbourne, Australia.
authors.forename: Blaine R
authors.initials: BR
authors.lastname: Roberts
authors.affiliation: Florey Institute, University of Melbourne, Australia; Department of Pathology, University of Melbourne, Australia.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: McAllum
authors.affiliation: Florey Institute, University of Melbourne, Australia; Department of Pathology, University of Melbourne, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Rhoads
authors.affiliation: Department of Statistics, Oregon State University, United States.
authors.forename: Cliff
authors.initials: C
authors.lastname: Pereira
authors.affiliation: Department of Neurology, University of Texas Southwestern, Dallas, Texas, United States.
authors.forename: Marjatta
authors.initials: M
authors.lastname: Son
authors.affiliation: Department of Neurology, University of Texas Southwestern, Dallas, Texas, United States.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Elliott
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States.
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Franco
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Estévez
authors.affiliation: Institut Pasteur de Montevideo, Uruguay.
authors.forename: Luis
authors.initials: L
authors.lastname: Barbeito
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States. Electronic address: joe.beckman@oregonstate.edu.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Beckman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D003300:Copper / Q000008:administration & dosage* / Q000378:metabolism*; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: C491962:Ccs protein, mouse; D018832:Molecular Chaperones; D003300:Copper; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV
keywords: Amyotrophic lateral sclerosis; CCS; Lou Gehrig; SOD1; Superoxide dismutase
references.citation: Science. 1999 Dec 24;286(5449):2498-500
references.pmid: 10617463
references.citation: Nat Neurosci. 2009 May;12(5):627-36
references.pmid: 19330001
references.citation: J Neurosci. 2014 Jun 4;34(23):8021-31
references.pmid: 24899723
references.citation: J Neurol Sci. 2014 Jan 15;336(1-2):1-7
references.pmid: 24269091
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):5074-9
references.pmid: 22416121
references.citation: Am J Hum Genet. 2010 Mar 12;86(3):343-52
references.pmid: 20170900
references.citation: Amyotroph Lateral Scler. 2008;9(1):4-15
references.pmid: 18273714
references.citation: J Mol Biol. 2008 Dec 12;384(2):540-55
references.pmid: 18840448
references.citation: PLoS One. 2012;7(8):e42277
references.pmid: 22879928
references.citation: J Exp Med. 2012 Apr 9;209(4):837-54
references.pmid: 22473957
references.citation: Brain Behav. 2013 Jul;3(4):431-57
references.pmid: 24381813
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5518-23
references.pmid: 15064408
references.citation: Neurobiol Dis. 2013 Jun;54:308-19
references.pmid: 23321002
references.citation: J Neurosci Res. 2002 Jan 1;67(1):21-9
references.pmid: 11754077
references.citation: Brain. 2006 Feb;129(Pt 2):451-64
references.pmid: 16330499
references.citation: J Biol Chem. 2002 Dec 6;277(49):47551-6
references.pmid: 12356748
references.citation: Ann N Y Acad Sci. 2014 May;1314:1-5
references.pmid: 24517364
references.citation: Nat Neurosci. 2010 Nov;13(11):1396-403
references.pmid: 20953194
references.citation: J Biol Chem. 2002 Aug 16;277(33):29626-33
references.pmid: 12050154
references.citation: J Biol Inorg Chem. 2002 Mar;7(3):249-59
references.pmid: 11935349
references.citation: Brain Behav. 2013 Jul;3(4):335-50
references.pmid: 24381807
references.citation: Anal Biochem. 2011 Aug 1;415(1):52-8
references.pmid: 21453670
references.citation: Biochemistry. 2000 Dec 5;39(48):14720-7
references.pmid: 11101286
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7142-7
references.pmid: 16636275
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):47-52
references.pmid: 22173633
references.citation: Anal Biochem. 1994 Sep;221(2):243-9
references.pmid: 7810863
references.citation: Nucl Med Biol. 2010 Apr;37(3):237-43
references.pmid: 20346863
references.citation: J Neurosci. 1998 May 1;18(9):3241-50
references.pmid: 9547233
references.citation: J Nutr. 2004 Aug;134(8):1984-8
references.pmid: 15284387
references.citation: J Biol Chem. 2011 Dec 23;286(51):44035-44
references.pmid: 22033929
references.citation: Cytogenet Cell Genet. 2000;88(1-2):35-7
references.pmid: 10773661
references.citation: J Pathol. 2015 Jun;236(2):241-50
references.pmid: 25639447
references.citation: J Neurosci. 2011 Nov 2;31(44):15826-37
references.pmid: 22049426
references.citation: J Neurochem. 1999 Jan;72(1):422-9
references.pmid: 9886096
references.citation: Acta Neuropathol. 2001 Oct;102(4):293-305
references.pmid: 11603803
references.citation: Prog Neurobiol. 2008 May;85(1):94-134
references.pmid: 18282652
references.citation: J Nutr. 1991 Mar;121(3):355-63
references.pmid: 1848285
references.citation: Antioxid Redox Signal. 2009 Jul;11(7):1627-39
references.pmid: 19309264
references.citation: J Nutr. 2002 Oct;132(10):3142-5
references.pmid: 12368408
references.citation: Neurobiol Dis. 2012 Jan;45(1):137-44
references.pmid: 21820513
references.citation: Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):E1102-11
references.pmid: 23487751
references.citation: J Biol Chem. 2008 May 2;283(18):12267-75
references.pmid: 18334481
references.citation: Mitochondrion. 2005 Apr;5(2):77-87
references.pmid: 16050975
references.citation: Science. 1994 Jun 17;264(5166):1772-5
references.pmid: 8209258
references.citation: Toxicology. 2007 Jan 5;229(1-2):33-41
references.pmid: 17097207
references.citation: Neurology. 2015 May 19;84(20):2033-9
references.pmid: 25904686
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Jun;4(2):62-73
references.pmid: 14506936
references.citation: J Biol Chem. 2011 Jan 28;286(4):2795-806
references.pmid: 21068388
references.citation: Nature. 2010 Jun 3;465(7298):645-8
references.pmid: 20463663
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6072-7
references.pmid: 17389365
references.citation: Amyotroph Lateral Scler Frontotemporal Degener. 2013 Dec;14(7-8):586-90
references.pmid: 23952668
references.citation: J Am Soc Mass Spectrom. 2013 Jan;24(1):115-24
references.pmid: 23247967