Increased Zinc and Manganese in Parallel with Neurodegeneration, Synaptic Protein Changes and Activation of Akt/GSK3 Signaling in Ovine CLN6 Neuronal Ceroid Lipofuscinosis

Katja M. Kanninen, Alexandra Grubman, Jodi Meyerowitz, Clare Duncan, Jiang Li Tan, Sarah J. Parker, Peter J. Crouch, Brett M. Paterson, James L. Hickey, Paul S. Donnelly, Irene Volitakis, Imke Tammen, David N Palmer, Anthony R White

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Article numbere58644
Pages (from-to)1-10
Number of pages10
JournalPLoS ONE
Volume8
Issue number3
DOIs
Publication statusPublished - 14 Mar 2013
Externally publishedYes

Cite this

Kanninen, Katja M. ; Grubman, Alexandra ; Meyerowitz, Jodi ; Duncan, Clare ; Tan, Jiang Li ; Parker, Sarah J. ; Crouch, Peter J. ; Paterson, Brett M. ; Hickey, James L. ; Donnelly, Paul S. ; Volitakis, Irene ; Tammen, Imke ; Palmer, David N ; White, Anthony R. / Increased Zinc and Manganese in Parallel with Neurodegeneration, Synaptic Protein Changes and Activation of Akt/GSK3 Signaling in Ovine CLN6 Neuronal Ceroid Lipofuscinosis. In: PLoS ONE. 2013 ; Vol. 8, No. 3. pp. 1-10.
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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.",
author = "Kanninen, {Katja M.} and Alexandra Grubman and Jodi Meyerowitz and Clare Duncan and Tan, {Jiang Li} and Parker, {Sarah J.} and Crouch, {Peter J.} and Paterson, {Brett M.} and Hickey, {James L.} and Donnelly, {Paul S.} and Irene Volitakis and Imke Tammen and Palmer, {David N} and White, {Anthony R}",
year = "2013",
month = "3",
day = "14",
doi = "10.1371/journal.pone.0058644",
language = "English",
volume = "8",
pages = "1--10",
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Kanninen, KM, Grubman, A, Meyerowitz, J, Duncan, C, Tan, JL, Parker, SJ, Crouch, PJ, Paterson, BM, Hickey, JL, Donnelly, PS, Volitakis, I, Tammen, I, Palmer, DN & White, AR 2013, 'Increased Zinc and Manganese in Parallel with Neurodegeneration, Synaptic Protein Changes and Activation of Akt/GSK3 Signaling in Ovine CLN6 Neuronal Ceroid Lipofuscinosis' PLoS ONE, vol. 8, no. 3, e58644, pp. 1-10. https://doi.org/10.1371/journal.pone.0058644

Increased Zinc and Manganese in Parallel with Neurodegeneration, Synaptic Protein Changes and Activation of Akt/GSK3 Signaling in Ovine CLN6 Neuronal Ceroid Lipofuscinosis. / Kanninen, Katja M.; Grubman, Alexandra; Meyerowitz, Jodi; Duncan, Clare; Tan, Jiang Li; Parker, Sarah J.; Crouch, Peter J.; Paterson, Brett M.; Hickey, James L.; Donnelly, Paul S.; Volitakis, Irene; Tammen, Imke; Palmer, David N; White, Anthony R.

In: PLoS ONE, Vol. 8, No. 3, e58644, 14.03.2013, p. 1-10.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Increased Zinc and Manganese in Parallel with Neurodegeneration, Synaptic Protein Changes and Activation of Akt/GSK3 Signaling in Ovine CLN6 Neuronal Ceroid Lipofuscinosis

AU - Kanninen, Katja M.

AU - Grubman, Alexandra

AU - Meyerowitz, Jodi

AU - Duncan, Clare

AU - Tan, Jiang Li

AU - Parker, Sarah J.

AU - Crouch, Peter J.

AU - Paterson, Brett M.

AU - Hickey, James L.

AU - Donnelly, Paul S.

AU - Volitakis, Irene

AU - Tammen, Imke

AU - Palmer, David N

AU - White, Anthony R

PY - 2013/3/14

Y1 - 2013/3/14

N2 - 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.

AB - 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.

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DO - 10.1371/journal.pone.0058644

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VL - 8

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JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

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