Document Detail


Enhanced survival of wild-type and Lurcher Purkinje cells in vitro following inhibition of conventional PKCs or stress-activated MAP kinase pathways.
MedLine Citation:
PMID:  23136008     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recent studies using both dissociated and organotypic cell cultures have shown that heterozygous Lurcher (Lc/+) Purkinje cells (PCs) grown in vitro share many of the same survival and morphological characteristics as Lc/+ PCs in vivo. We have used this established tissue culture system as a valuable model for studying cell death mechanisms in a relatively simple system where neurodegeneration is induced by a constitutive cation leak mediated by the Lurcher mutation in the δ2 glutamate receptor (GluRδ2). In this study, Ca(++) imaging and immunocytochemistry studies indicate that intracellular levels of Ca(++) are chronically increased in Lc/+ PCs and the concentration and/or distribution of the conventional PKCγ isoform is altered in degenerating Lc/+ PCs. To begin to characterize the molecular mechanisms that regulate Lc/+ PC death, the contributions of conventional PKC pathways and of two MAP kinase family members, JNK and p38, were examined in slice cultures from wild-type and Lc/+ mutant mouse cerebellum. Cerebellar slice cultures from P0 pups were treated with either a conventional PKC inhibitor, a JNK inhibitor, or a p38 inhibitor either from 0 to 14 or 7 to 14 DIV. Treatment with either of the three inhibitors from 0 DIV significantly increased wild type and Lc/+ PC survival through 14 DIV, but only Lc/+ PC survival was significantly increased following treatments from 7 to 14 DIV. The results suggest that multiple PC death pathways are induced by the physical trauma of making organotypic slice cultures, naturally-occurring postnatal cell death, and the GluRδ2 (Lc) mutation.
Authors:
Hadi S Zanjani; Ann M Lohof; Rebecca McFarland; Michael W Vogel; Jean Mariani
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cerebellum (London, England)     Volume:  12     ISSN:  1473-4230     ISO Abbreviation:  Cerebellum     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-02     Completed Date:  2013-12-04     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  101089443     Medline TA:  Cerebellum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  377-89     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Animals, Newborn
Calbindins / metabolism
Calcium / metabolism
Caspase 3 / metabolism
Cell Survival / drug effects,  genetics
Cerebellum / cytology*
Enzyme Inhibitors / pharmacology
Female
Gene Expression Regulation, Enzymologic / drug effects,  genetics
Male
Mice
Mice, Inbred CBA
Mice, Transgenic
Mitogen-Activated Protein Kinases / metabolism*
Organ Culture Techniques
Protein Kinase C / metabolism*
Purkinje Cells / drug effects*
Receptors, Glutamate / genetics*
Signal Transduction / drug effects*,  genetics
Grant Support
ID/Acronym/Agency:
NS 34309/NS/NINDS NIH HHS; R01 NS034309/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Calbindins; 0/Enzyme Inhibitors; 0/Receptors, Glutamate; 0/glutamate receptor delta 2; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.4.22.-/Caspase 3; SY7Q814VUP/Calcium
Comments/Corrections

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