Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis

Katja M. Kanninen, Alexandra Grubman, Aphrodite Caragounis, Clare Duncan, Sarah J. Parker, Grace E. Lidgerwood, Irene Volitakis, George Ganio, Peter J. Crouch, Anthony R. White

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Neuronal ceroid lipofuscinoses, the most common fatal childhood neurodegenerative illnesses, share many features with more prevalent neurodegenerative diseases. Neuronal ceroid lipofuscinoses are caused by mutations in CLN genes. CLN6 encodes a transmembrane endoplasmic reticulum protein with no known function. We characterized the behavioural phenotype of spontaneous mutant mice modeling CLN6 disease, and demonstrate progressive motor and visual decline and reduced lifespan in these mice, consistent with symptoms observed in neuronal ceroid lipofuscinosis patients. Alterations to biometal homeostasis are known to play a critical role in pathology in Alzheimer's, Parkinson's, Huntington's and motor neuron diseases. We have previously shown accumulation of the biometals, zinc, copper, manganese and cobalt, in CLN6Merino and South Hampshire sheep at the age of symptom onset. Here we determine the physiological and disease-associated expression of CLN6, demonstrating regional CLN6 transcript loss, and concurrent accumulation of the same biometals in the CNS and the heart of presymptomatic CLN6 mice. Furthermore, increased expression of the ER/Golgi-localized cation transporter protein, Zip7, was detected in cerebellar Purkinje cells and whole brain fractions. Purkinje cells not only control motor function, an early symptomatic change in the CLN6 mice, but also display prominent neuropathological changes in mouse models and patients with different forms of neuronal ceroid lipofuscinoses. Whole brain fractionation analysis revealed biometal accumulation in fractions expressing markers for ER, Golgi, endosomes and lysosomes of CLN6 brains. These data are consistent with a link between CLN6 expression and biometal homeostasis in CLN6 disease, and provide further support for altered cation transporter regulation as a key factor in neurodegeneration.
Original languageEnglish
Pages (from-to)635-646
Number of pages12
JournalBiology Open
Volume2
Issue number6
DOIs
Publication statusPublished - 15 Jun 2013
Externally publishedYes

Keywords

  • Biometal homeostasis
  • CLN6
  • Metal transporter
  • Neurodegeneration
  • Neuronal ceroid lipofuscinoses

Cite this

Kanninen, K. M., Grubman, A., Caragounis, A., Duncan, C., Parker, S. J., Lidgerwood, G. E., ... White, A. R. (2013). Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis. Biology Open, 2(6), 635-646. https://doi.org/10.1242/bio.20134804
Kanninen, Katja M. ; Grubman, Alexandra ; Caragounis, Aphrodite ; Duncan, Clare ; Parker, Sarah J. ; Lidgerwood, Grace E. ; Volitakis, Irene ; Ganio, George ; Crouch, Peter J. ; White, Anthony R. / Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis. In: Biology Open. 2013 ; Vol. 2, No. 6. pp. 635-646.
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abstract = "Neuronal ceroid lipofuscinoses, the most common fatal childhood neurodegenerative illnesses, share many features with more prevalent neurodegenerative diseases. Neuronal ceroid lipofuscinoses are caused by mutations in CLN genes. CLN6 encodes a transmembrane endoplasmic reticulum protein with no known function. We characterized the behavioural phenotype of spontaneous mutant mice modeling CLN6 disease, and demonstrate progressive motor and visual decline and reduced lifespan in these mice, consistent with symptoms observed in neuronal ceroid lipofuscinosis patients. Alterations to biometal homeostasis are known to play a critical role in pathology in Alzheimer's, Parkinson's, Huntington's and motor neuron diseases. We have previously shown accumulation of the biometals, zinc, copper, manganese and cobalt, in CLN6Merino and South Hampshire sheep at the age of symptom onset. Here we determine the physiological and disease-associated expression of CLN6, demonstrating regional CLN6 transcript loss, and concurrent accumulation of the same biometals in the CNS and the heart of presymptomatic CLN6 mice. Furthermore, increased expression of the ER/Golgi-localized cation transporter protein, Zip7, was detected in cerebellar Purkinje cells and whole brain fractions. Purkinje cells not only control motor function, an early symptomatic change in the CLN6 mice, but also display prominent neuropathological changes in mouse models and patients with different forms of neuronal ceroid lipofuscinoses. Whole brain fractionation analysis revealed biometal accumulation in fractions expressing markers for ER, Golgi, endosomes and lysosomes of CLN6 brains. These data are consistent with a link between CLN6 expression and biometal homeostasis in CLN6 disease, and provide further support for altered cation transporter regulation as a key factor in neurodegeneration.",
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Kanninen, KM, Grubman, A, Caragounis, A, Duncan, C, Parker, SJ, Lidgerwood, GE, Volitakis, I, Ganio, G, Crouch, PJ & White, AR 2013, 'Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis' Biology Open, vol. 2, no. 6, pp. 635-646. https://doi.org/10.1242/bio.20134804

Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis. / Kanninen, Katja M.; Grubman, Alexandra; Caragounis, Aphrodite; Duncan, Clare; Parker, Sarah J.; Lidgerwood, Grace E.; Volitakis, Irene; Ganio, George; Crouch, Peter J.; White, Anthony R.

In: Biology Open, Vol. 2, No. 6, 15.06.2013, p. 635-646.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis

AU - Kanninen, Katja M.

AU - Grubman, Alexandra

AU - Caragounis, Aphrodite

AU - Duncan, Clare

AU - Parker, Sarah J.

AU - Lidgerwood, Grace E.

AU - Volitakis, Irene

AU - Ganio, George

AU - Crouch, Peter J.

AU - White, Anthony R.

PY - 2013/6/15

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N2 - Neuronal ceroid lipofuscinoses, the most common fatal childhood neurodegenerative illnesses, share many features with more prevalent neurodegenerative diseases. Neuronal ceroid lipofuscinoses are caused by mutations in CLN genes. CLN6 encodes a transmembrane endoplasmic reticulum protein with no known function. We characterized the behavioural phenotype of spontaneous mutant mice modeling CLN6 disease, and demonstrate progressive motor and visual decline and reduced lifespan in these mice, consistent with symptoms observed in neuronal ceroid lipofuscinosis patients. Alterations to biometal homeostasis are known to play a critical role in pathology in Alzheimer's, Parkinson's, Huntington's and motor neuron diseases. We have previously shown accumulation of the biometals, zinc, copper, manganese and cobalt, in CLN6Merino and South Hampshire sheep at the age of symptom onset. Here we determine the physiological and disease-associated expression of CLN6, demonstrating regional CLN6 transcript loss, and concurrent accumulation of the same biometals in the CNS and the heart of presymptomatic CLN6 mice. Furthermore, increased expression of the ER/Golgi-localized cation transporter protein, Zip7, was detected in cerebellar Purkinje cells and whole brain fractions. Purkinje cells not only control motor function, an early symptomatic change in the CLN6 mice, but also display prominent neuropathological changes in mouse models and patients with different forms of neuronal ceroid lipofuscinoses. Whole brain fractionation analysis revealed biometal accumulation in fractions expressing markers for ER, Golgi, endosomes and lysosomes of CLN6 brains. These data are consistent with a link between CLN6 expression and biometal homeostasis in CLN6 disease, and provide further support for altered cation transporter regulation as a key factor in neurodegeneration.

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