Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14

Ji, Jingmin and Hassler, Melanie L. and Shimobayashi, Etsuko and Paka, Nagendher and Streit, Raphael and Kapfhammer, Josef P.. (2014) Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14. Neurobiology of disease, 70. pp. 1-11.

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Official URL: https://edoc.unibas.ch/62148/

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Spinocerebellar ataxias (SCAs) are hereditary diseases leading to Purkinje cell degeneration and cerebellar dysfunction. Most forms of SCA are caused by expansion of CAG repeats similar to other polyglutamine disorders such as Huntington's disease. In contrast, in the autosomal dominant SCA-14 the disease is caused by mutations in the protein kinase C gamma (PKCgamma) gene which is a well characterized signaling molecule in cerebellar Purkinje cells. The study of SCA-14, therefore, offers the unique opportunity to reveal the molecular and pathological mechanism eventually leading to Purkinje cell dysfunction and degeneration. We have created a mouse model of SCA-14 in which PKCgamma protein with a mutation found in SCA-14 is specifically expressed in cerebellar Purkinje cells. We find that in mice expressing the mutated PKCgamma protein the morphology of Purkinje cells in cerebellar slice cultures is drastically altered and mimics closely the morphology seen after pharmacological PKC activation. Similar morphological abnormalities were seen in localized areas of the cerebellum of juvenile transgenic mice in vivo. In adult transgenic mice there is evidence for some localized loss of Purkinje cells but there is no overall cerebellar atrophy. Transgenic mice show a mild cerebellar ataxia revealed by testing on the rotarod and on the walking beam. Our findings provide evidence for both an increased PKCgamma activity in Purkinje cells in vivo and for pathological changes typical for cerebellar disease thus linking the increased and dysregulated activity of PKCgamma tightly to the development of cerebellar disease in SCA-14 and possibly also in other forms of SCA.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Anatomy > Developmental Neurobiology and Regeneration (Kapfhammer)
UniBasel Contributors:Kapfhammer, Josef
Item Type:Article, refereed
Article Subtype:Research Article
ISSN: 0969-9961
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Jul 2020 14:38
Deposited On:28 Jul 2020 14:38

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