title: Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14.
abstract: 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 (PKCγ) 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 PKCγ protein with a mutation found in SCA-14 is specifically expressed in cerebellar Purkinje cells. We find that in mice expressing the mutated PKCγ 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 PKCγ activity in Purkinje cells in vivo and for pathological changes typical for cerebellar disease thus linking the increased and dysregulated activity of PKCγ tightly to the development of cerebellar disease in SCA-14 and possibly also in other forms of SCA.
authors.affiliation: Anatomical Institute, Department of Biomedicine Basel, University of Basel, Pestalozzistr, 20, CH-4056 Basel, Switzerland.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Ji
authors.affiliation: Anatomical Institute, Department of Biomedicine Basel, University of Basel, Pestalozzistr, 20, CH-4056 Basel, Switzerland.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Hassler
authors.affiliation: Anatomical Institute, Department of Biomedicine Basel, University of Basel, Pestalozzistr, 20, CH-4056 Basel, Switzerland.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Shimobayashi
authors.affiliation: Anatomical Institute, Department of Biomedicine Basel, University of Basel, Pestalozzistr, 20, CH-4056 Basel, Switzerland.
authors.forename: Nagendher
authors.initials: N
authors.lastname: Paka
authors.affiliation: Anatomical Institute, Department of Biomedicine Basel, University of Basel, Pestalozzistr, 20, CH-4056 Basel, Switzerland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Streit
authors.affiliation: Anatomical Institute, Department of Biomedicine Basel, University of Basel, Pestalozzistr, 20, CH-4056 Basel, Switzerland. Electronic address: Josef.Kapfhammer@unibas.ch.
authors.forename: Josef P
authors.initials: JP
authors.lastname: Kapfhammer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002531:Cerebellum / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D003712:Dendrites / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000201:enzymology* / Q000473:pathology*; D045442:Rotarod Performance Test; D020754:Spinocerebellar Ataxias; D013132:Spinocerebellar Degenerations / Q000201:enzymology* / Q000473:pathology*; D046509:Tissue Culture Techniques
chemical_list: C087857:protein kinase C gamma; D011493:Protein Kinase C
keywords: Protein kinase C gamma; Purkinje cell dendritic development; Spinocerebellar ataxia type 14; Transgenic mouse model