Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis
Summary 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 wit...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2013-05-01
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| Series: | Biology Open |
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| Online Access: | http://bio.biologists.org/content/2/6/635 |
| _version_ | 1818436209685299200 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Katja M. Kanninen |
| collection | DOAJ |
| description | Summary
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 CLN6 Merino 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. |
| first_indexed | 2024-12-14T17:05:09Z |
| format | Article |
| id | doaj.art-7d3ab43bc30e4045897d16317b6c962d |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-14T17:05:09Z |
| publishDate | 2013-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-7d3ab43bc30e4045897d16317b6c962d2022-12-21T22:53:44ZengThe Company of BiologistsBiology Open2046-63902013-05-012663564610.1242/bio.2013480420134804Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosisKatja M. Kanninen0Alexandra Grubman1Aphrodite Caragounis2Clare Duncan3Sarah J. Parker4Grace E. Lidgerwood5Irene Volitakis6George Ganio7Peter J. Crouch8Anthony R. White9 Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia Summary 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 CLN6 Merino 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.http://bio.biologists.org/content/2/6/635NeurodegenerationBiometal homeostasisNeuronal ceroid lipofuscinosesCLN6Metal transporter |
| spellingShingle | 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 Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis Biology Open Neurodegeneration Biometal homeostasis Neuronal ceroid lipofuscinoses CLN6 Metal transporter |
| title | Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis |
| title_full | Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis |
| title_fullStr | Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis |
| title_full_unstemmed | Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis |
| title_short | Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis |
| title_sort | altered biometal homeostasis is associated with cln6 mrna loss in mouse neuronal ceroid lipofuscinosis |
| topic | Neurodegeneration Biometal homeostasis Neuronal ceroid lipofuscinoses CLN6 Metal transporter |
| url | http://bio.biologists.org/content/2/6/635 |
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