Defective Retrotranslocation Causes Loss of Anti-Bax Function in Human Familial Prion Protein Mutants
| Autor: | Julie Jodoin, Stéphanie Laroche-Pierre, Cynthia G. Goodyer, Andréa C. LeBlanc |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cytoplasm
Protein Folding Programmed cell death Glycosylphosphatidylinositols Prions animal diseases Mutant Apoptosis Biology Transfection medicine.disease_cause Prion Diseases Cell membrane Bcl-2-associated X protein Cell Line Tumor medicine Animals Humans Cells Cultured bcl-2-Associated X Protein Mutation General Neuroscience Cell Membrane Wild type Articles Molecular biology nervous system diseases Transport protein Protein Transport medicine.anatomical_structure biology.protein |
| Zdroj: | The Journal of Neuroscience. 27:5081-5091 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.0957-07.2007 |
| Popis: | Prion protein (PrP) inhibits the activation of proapoptotic Bax in primary human neurons and MCF-7 cells. Because neuronal apoptosis occurs in human prion diseases, here we examine the anti-Bax function of familial PrP mutants. All Creutzfeldt-Jakob disease and fatal familial insomnia-associated prion protein mutations partially or completely lose the anti-Bax function in human neurons and, except for A117V and V203I, in MCF-7 cells. The ability of the mutants to protect against Bax-mediated cell death is divided into three groups: (1) group I, retention of anti-Bax function in both the Val129and Met129mutants; (2) group II, retention of anti-Bax function only in Val129mutants; and (3) group III, reduction or no anti-Bax function in Val129and Met129mutants. The loss of anti-Bax function in these PrP mutants correlates completely with a significant decrease in the production of cytosolic PrP, a form of PrP shown previously to have anti-Bax function in human neurons. Cotransfection of the full-length PrP mutants with wild-type or mutant cytosolic PrP, but not with wild type full-length PrP, rescues the anti-Bax function of PrP. The results show that the failure of PrP mutants to produce cytosolic PrP is responsible for the loss of anti-Bax function and that the effect of the PrP mutants is dominant over wild-type PrP. Furthermore, these results imply that misfolded PrP that escapes retrotranslocation could accumulate at the cell surface and cause neuronal dysfunction. |
| Databáze: | OpenAIRE |
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