Deregulation of biometal homeostasis: The missing link for neuronal ceroid lipofuscinoses?

Alexandra Grubman, Eveliina Pollari, Clare Duncan, Aphrodite Caragounis, Tea Blom, Irene Volitakis, Andrew M S Wong, Jonathan D Cooper, Peter J. Crouch, Jari Koistinaho, Anu Jalanko, Anthony R White, Katja M. Kanninen

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)932-943
Number of pages12
JournalMetallomics
Volume6
Issue number4
DOIs
Publication statusPublished - 6 Mar 2014
Externally publishedYes

Cite this

Grubman, A., Pollari, E., Duncan, C., Caragounis, A., Blom, T., Volitakis, I., ... Kanninen, K. M. (2014). Deregulation of biometal homeostasis: The missing link for neuronal ceroid lipofuscinoses? Metallomics, 6(4), 932-943. https://doi.org/10.1039/c4mt00032c
Grubman, Alexandra ; Pollari, Eveliina ; Duncan, Clare ; Caragounis, Aphrodite ; Blom, Tea ; Volitakis, Irene ; Wong, Andrew M S ; Cooper, Jonathan D ; Crouch, Peter J. ; Koistinaho, Jari ; Jalanko, Anu ; White, Anthony R ; Kanninen, Katja M. / Deregulation of biometal homeostasis : The missing link for neuronal ceroid lipofuscinoses?. In: Metallomics. 2014 ; Vol. 6, No. 4. pp. 932-943.
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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.",
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Grubman, A, Pollari, E, Duncan, C, Caragounis, A, Blom, T, Volitakis, I, Wong, AMS, Cooper, JD, Crouch, PJ, Koistinaho, J, Jalanko, A, White, AR & Kanninen, KM 2014, 'Deregulation of biometal homeostasis: The missing link for neuronal ceroid lipofuscinoses?' Metallomics, vol. 6, no. 4, pp. 932-943. https://doi.org/10.1039/c4mt00032c

Deregulation of biometal homeostasis : The missing link for neuronal ceroid lipofuscinoses? / Grubman, Alexandra; Pollari, Eveliina; Duncan, Clare; Caragounis, Aphrodite; Blom, Tea; Volitakis, Irene; Wong, Andrew M S; Cooper, Jonathan D; Crouch, Peter J.; Koistinaho, Jari; Jalanko, Anu; White, Anthony R; Kanninen, Katja M.

In: Metallomics, Vol. 6, No. 4, 06.03.2014, p. 932-943.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Deregulation of biometal homeostasis

T2 - The missing link for neuronal ceroid lipofuscinoses?

AU - Grubman, Alexandra

AU - Pollari, Eveliina

AU - Duncan, Clare

AU - Caragounis, Aphrodite

AU - Blom, Tea

AU - Volitakis, Irene

AU - Wong, Andrew M S

AU - Cooper, Jonathan D

AU - Crouch, Peter J.

AU - Koistinaho, Jari

AU - Jalanko, Anu

AU - White, Anthony R

AU - Kanninen, Katja M.

PY - 2014/3/6

Y1 - 2014/3/6

N2 - 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.

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