title: Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder.
abstract: BACKGROUND
  Aberrant biometal metabolism is a key feature of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Metal modulating compounds are promising therapeutics for neurodegeneration, but their mechanism of action remains poorly understood. Neuronal ceroid lipofuscinoses (NCLs), caused by mutations in CLN genes, are fatal childhood neurodegenerative lysosomal storage diseases without a cure. We previously showed biometal accumulation in ovine and murine models of the CLN6 variant NCL, but the mechanism is unknown. This study extended the concept that alteration of biometal functions is involved in pathology in these disorders, and investigated molecular mechanisms underlying impaired biometal trafficking in CLN6 disease.
  
  
  RESULTS
  We observed significant region-specific biometal accumulation and deregulation of metal trafficking pathways prior to disease onset in CLN6 affected sheep. Substantial progressive loss of the ER/Golgi-resident Zn transporter, Zip7, which colocalized with the disease-associated protein, CLN6, may contribute to the subcellular deregulation of biometal homeostasis in NCLs. Importantly, the metal-complex, ZnII(atsm), induced Zip7 upregulation, promoted Zn redistribution and restored Zn-dependent functions in primary mouse Cln6 deficient neurons and astrocytes.
  
  
  CONCLUSIONS
  This study demonstrates the central role of the metal transporter, Zip7, in the aberrant biometal metabolism of CLN6 variants of NCL and further highlights the key contribution of deregulated biometal trafficking to the pathology of neurodegenerative diseases. Importantly, our results suggest that ZnII(atsm) may be a candidate for therapeutic trials for NCLs.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grubman
authors.forename: Grace E
authors.initials: GE
authors.lastname: Lidgerwood
authors.forename: Clare
authors.initials: C
authors.lastname: Duncan
authors.forename: Laura
authors.initials: L
authors.lastname: Bica
authors.forename: Jiang-Li
authors.initials: JL
authors.lastname: Tan
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parker
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Caragounis
authors.forename: Jodi
authors.initials: J
authors.lastname: Meyerowitz
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Diane
authors.initials: D
authors.lastname: Moujalled
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Liddell
authors.forename: James L
authors.initials: JL
authors.lastname: Hickey
authors.forename: Malcolm
authors.initials: M
authors.lastname: Horne
authors.forename: Shoshanah
authors.initials: S
authors.lastname: Longmuir
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Imke
authors.initials: I
authors.lastname: Tammen
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, VIC 3010, Australia. arwhite@unimelb.edu.au.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Katja M
authors.initials: KM
authors.lastname: Kanninen
mesh_terms: D000367:Age Factors; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D001692:Biological Transport / Q000235:genetics*; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012756:Sheep; D014335:Tropomyosin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D015032:Zinc / Q000494:pharmacology
chemical_list: C447500:CLN6 protein, human; D027682:Cation Transport Proteins; D004151:Dipeptides; D008565:Membrane Proteins; D008670:Metals; C102227:SLC39A7 protein, human; D014335:Tropomyosin; C504421:alanine-serine-tropomyosin; D000469:Alkaline Phosphatase; D015032:Zinc