title: Zn II(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism.
abstract: Mutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zinc(II) [Zn(II)(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the Zn(II)(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of Zn(II)(atsm) in the presence of Cu to form the Cu-analogue Cu(II)(atsm), indicating that the observed therapeutic effects for Zn(II)(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: McAllum
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Blaine R
authors.initials: BR
authors.lastname: Roberts
authors.affiliation: School of Chemistry and Bio21 Institute, The University of Melbourne, Victoria 3010, Australia.
authors.forename: James L
authors.initials: JL
authors.lastname: Hickey
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Theresa N
authors.initials: TN
authors.lastname: Dang
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grubman
authors.affiliation: School of Chemistry and Bio21 Institute, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Liddell
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia. Electronic address: pjcrouch@unimelb.edu.au.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D056831:Coordination Complexes / Q000627:therapeutic use*; D003300:Copper / Q000378:metabolism*; D004195:Disease Models, Animal; D008124:Locomotion / Q000187:drug effects; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000235:genetics; D013882:Thiosemicarbazones / Q000494:pharmacology / Q000627:therapeutic use; D015032:Zinc / Q000378:metabolism
chemical_list: C420686:(2,3-butanedione bis(N(4)-dimethylthiosemicarbazone))zinc(II); D056831:Coordination Complexes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; D003300:Copper; C470429:SOD1 G37R protein, mouse; D013482:Superoxide Dismutase; D015032:Zinc; C029892:cupric chloride
keywords: Amyotrophic lateral sclerosis (ALS); Bisthiosemicarbazone (btsc); Copper; Copper/zinc-superoxide dismutase (SOD1); Inductively coupled plasma mass spectrometry (ICP-MS); Metal; Mouse model; Therapeutic; Transmetallation; Zinc