Implicating Calpain in Tau-Mediated Toxicity In Vivo
| Autor: | Sarah L. DeVos, James B. Reinecke, Samantha Fleming, Amanda M. Shepard, Don N. Tait, Michelle L. Steinhilb, James P. McGrath, Michael S. Vincent, Dustin K. Goncharoff |
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| Rok vydání: | 2011 |
| Předmět: |
Proteolysis
Blotting Western Tau protein lcsh:Medicine tau Proteins Eye Animals Genetically Modified 03 medical and health sciences Model Organisms 0302 clinical medicine Neurobiology of Disease and Regeneration mental disorders Genetics medicine Animals Drosophila Proteins lcsh:Science Biology Cells Cultured 030304 developmental biology Neurons 0303 health sciences Multidisciplinary biology medicine.diagnostic_test Calpain Drosophila Melanogaster lcsh:R Neurotoxicity Neurodegenerative Diseases Animal Models medicine.disease Molecular biology 3. Good health Disease Models Animal Tauopathies Cell culture Genetics of Disease Mutation Microscopy Electron Scanning biology.protein lcsh:Q Tauopathy Alzheimer's disease 030217 neurology & neurosurgery Drosophila Protein Research Article Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Vol 6, Iss 8, p e23865 (2011) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0023865 |
| Popis: | Alzheimer's disease and other related neurodegenerative disorders known as tauopathies are characterized by the accumulation of abnormally phosphorylated and aggregated forms of the microtubule-associated protein tau. Several laboratories have identified a 17 kD proteolytic fragment of tau in degenerating neurons and in numerous cell culture models that is generated by calpain cleavage and speculated to contribute to tau toxicity. In the current study, we employed a Drosophila tauopathy model to investigate the importance of calpain-mediated tau proteolysis in contributing to tau neurotoxicity in an animal model of human neurodegenerative disease. We found that mutations that disrupted endogenous calpainA or calpainB activity in transgenic flies suppressed tau toxicity. Expression of a calpain-resistant form of tau in Drosophila revealed that mutating the putative calpain cleavage sites that produce the 17 kD fragment was sufficient to abrogate tau toxicity in vivo. Furthermore, we found significant toxicity in the fly retina associated with expression of only the 17 kD tau fragment. Collectively, our data implicate calpain-mediated proteolysis of tau as an important pathway mediating tau neurotoxicity in vivo. |
| Databáze: | OpenAIRE |
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