title: Deregulation of biometal homeostasis: the missing link for neuronal ceroid lipofuscinoses?
abstract: Neuronal ceroid lipofuscinoses (NCLs), a group of genetically distinct fatal neurodegenerative disorders with no treatment or cure, are clinically characterised by progressive motor and visual decline leading to premature death. While the underlying pathological mechanisms are yet to be precisely determined, the diseases share several common features including inflammation, lysosomal lipofuscin deposits and lipid abnormalities. An important hallmark of most common neurodegenerative disorders including Alzheimer's, Parkinson's and motor neuron diseases is deregulation of biologically active metal homeostasis. Metals such as zinc, copper and iron are critical enzyme cofactors and are important for synaptic transmission in the brain, but can mediate oxidative neurotoxicity when homeostatic regulatory mechanisms fail. We previously demonstrated biometal accumulation and altered biometal transporter expression in 3 animal models of CLN6 NCL disease. In this study we investigated the hypothesis that altered biometal homeostasis may be a feature of NCLs in general using 3 additional animal models of CLN1, CLN3 and CLN5 disease. We demonstrated significant accumulation of the biometals zinc, copper, manganese, iron and cobalt in these mice. Patterns of biometal accumulation in each model preceded significant neurodegeneration, and paralleled the relative severity of disease previously described for each model. Additionally, we observed deregulation of transcripts encoding the anti-oxidant protein, metallothionein (Mt), indicative of disruptions to biometal homeostasis. These results demonstrate that altered biometal homeostasis is a key feature of at least 4 genetically distinct forms of NCL disease.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grubman
authors.forename: Eveliina
authors.initials: E
authors.lastname: Pollari
authors.forename: Clare
authors.initials: C
authors.lastname: Duncan
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Caragounis
authors.forename: Tea
authors.initials: T
authors.lastname: Blom
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cooper
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Katja M
authors.initials: KM
authors.lastname: Kanninen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003035:Cobalt / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D006706:Homeostasis; D007501:Iron / Q000378:metabolism; D051907:Lysosomal Membrane Proteins; D008345:Manganese / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D019216:Metals, Heavy / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015032:Zinc / Q000378:metabolism
chemical_list: C102229:CLN3 protein, mouse; C488572:Cln5 protein, mouse; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D019216:Metals, Heavy; D018832:Molecular Chaperones; D003035:Cobalt; D008345:Manganese; D003300:Copper; D008668:Metallothionein; D007501:Iron; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D015032:Zinc