title: Increased zinc and manganese in parallel with neurodegeneration, synaptic protein changes and activation of Akt/GSK3 signaling in ovine CLN6 neuronal ceroid lipofuscinosis.
abstract: Mutations in the CLN6 gene cause a variant late infantile form of neuronal ceroid lipofuscinosis (NCL; Batten disease). CLN6 loss leads to disease clinically characterized by vision impairment, motor and cognitive dysfunction, and seizures. Accumulating evidence suggests that alterations in metal homeostasis and cellular signaling pathways are implicated in several neurodegenerative and developmental disorders, yet little is known about their role in the NCLs. To explore the disease mechanisms of CLN6 NCL, metal concentrations and expression of proteins implicated in cellular signaling pathways were assessed in brain tissue from South Hampshire and Merino CLN6 sheep. Analyses revealed increased zinc and manganese concentrations in affected sheep brain in those regions where neuroinflammation and neurodegeneration first occur. Synaptic proteins, the metal-binding protein metallothionein, and the Akt/GSK3 and ERK/MAPK cellular signaling pathways were also altered. These results demonstrate that altered metal concentrations, synaptic protein changes, and aberrant modulation of cellular signaling pathways are characteristic features in the CLN6 ovine form of NCL.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria, Australia. katja.kanninen@uef.fi
authors.forename: Katja M
authors.initials: KM
authors.lastname: Kanninen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grubman
authors.forename: Jodi
authors.initials: J
authors.lastname: Meyerowitz
authors.forename: Clare
authors.initials: C
authors.lastname: Duncan
authors.forename: Jiang-Li
authors.initials: JL
authors.lastname: Tan
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parker
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Brett M
authors.initials: BM
authors.lastname: Paterson
authors.forename: James L
authors.initials: JL
authors.lastname: Hickey
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Imke
authors.initials: I
authors.lastname: Tammen
authors.forename: David N
authors.initials: DN
authors.lastname: Palmer
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008345:Manganese / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D008668:Metallothionein / Q000378:metabolism; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D008345:Manganese; D008668:Metallothionein; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D015032:Zinc