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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / metabolism
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Brain / pathology
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Disease Models, Animal
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Glycogen Synthase Kinase 3 / metabolism
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Manganese / metabolism*
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Membrane Proteins / genetics*
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Metallothionein / metabolism
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Mutation
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Neuronal Ceroid-Lipofuscinoses / genetics
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Neuronal Ceroid-Lipofuscinoses / metabolism*
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Neuronal Ceroid-Lipofuscinoses / pathology*
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Sheep
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Signal Transduction*
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Synapses / metabolism*
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Zinc / metabolism*
Substances
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Membrane Proteins
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Manganese
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Metallothionein
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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Zinc
Grants and funding
KMK was supported by the Sigrid Juselius Foundation, the Academy of Finland, the Paulo Foundation and the Maud Kuistila Memorial Foundation. ARW was supported by an Australian Research Council ARC Future Fellowship. This work was supported by funding from the National Health and Medical Research Council of Australia. The work at Lincoln University was supported in part by the Neurological Foundation of New Zealand and the Batten Disease Support and Research Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.