Calcineurin determines toxic versus beneficial responses to alpha-synuclein
| Autor: | Pavan K. Auluck, Hanna Kim, Xiaohui Yan, Gabriela Caraveo, Kim A. Caldwell, Martin Soste, Paola Picotti, Chee Yeun Chung, Valeriya Baru, Luke Whitesell, Eugene V. Mosharov, David T. Yue, Manu Ben-Johny, Guy A. Caldwell, David Sulzer, Susan Lindquist |
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| Rok vydání: | 2014 |
| Předmět: |
Lewy Body Disease
Saccharomyces cerevisiae Proteins Calcineurin Inhibitors Models Neurological Phosphatase Mice Transgenic Saccharomyces cerevisiae Biology Tacrolimus Mice chemistry.chemical_compound Calmodulin Animals Humans Calcium Signaling Cells Cultured Neuroinflammation Calcium signaling Neurons Alpha-synuclein Synucleinopathies Multidisciplinary NFATC Transcription Factors Calcineurin Parkinson Disease NFAT Phosphoric Monoester Hydrolases Recombinant Proteins Rats 3. Good health PNAS Plus chemistry Biochemistry Gene Knockdown Techniques alpha-Synuclein |
| Zdroj: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Proceedings of the National Academy of Sciences of the United States of America |
| DOI: | 10.1073/pnas.1413201111 |
| Popis: | Significance Ca 2+ homeostasis is indispensable for the well being of all living organisms. Ca 2+ homeostasis is disrupted by α-synuclein (α-syn), whose misfolding plays a major role in neurodegenerative diseases termed synucleinopathies, such as Parkinson disease. We report that α-syn can induce sustained and highly elevated levels of cytoplasmic Ca 2+ , thereby activating a calcineurin (CN) cascade that results in toxicity. CN is a highly conserved Ca 2+ –calmodulin (CaM)-dependent phosphatase critical for sensing Ca 2+ concentrations and transducing that information into cellular responses. Limiting, but not eliminating, the availability of CaM, CN and/or CN substrates directly with genetic or pharmacological tools shifts the α-syn–induced CN cascade to a protective mode. This has mechanistic implications for CN's activity and provides a therapeutic venue for the treatment of synucleinopathies. |
| Databáze: | OpenAIRE |
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