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- Fangfang Bi
- Departments of aPathology, Anatomy, and Cell Biology, and
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- Cao Huang
- Departments of aPathology, Anatomy, and Cell Biology, and
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- Jianbin Tong
- Departments of aPathology, Anatomy, and Cell Biology, and
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- Guang Qiu
- Departments of aPathology, Anatomy, and Cell Biology, and
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- Bo Huang
- Neurology, Thomas Jefferson University, Philadelphia, PA 19107;
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- Qinxue Wu
- Departments of aPathology, Anatomy, and Cell Biology, and
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- Fang Li
- Departments of aPathology, Anatomy, and Cell Biology, and
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- Zuoshang Xu
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605; and
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- Robert Bowser
- Divisions of Neurology and Neurobiology, Barrow Neurological Institute and St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013
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- Xu-Gang Xia
- Departments of aPathology, Anatomy, and Cell Biology, and
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- Hongxia Zhou
- Departments of aPathology, Anatomy, and Cell Biology, and
書誌事項
- 公開日
- 2013-02-19
- DOI
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- 10.1073/pnas.1218497110
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p>Glial reaction is a common feature of neurodegenerative diseases. Recent studies have suggested that reactive astrocytes gain neurotoxic properties, but exactly how reactive astrocytes contribute to neurotoxicity remains to be determined. Here, we identify lipocalin 2 (lcn2) as an inducible factor that is secreted by reactive astrocytes and that is selectively toxic to neurons. We show that lcn2 is induced in reactive astrocytes in transgenic rats with neuronal expression of mutant human TAR DNA-binding protein 43 (TDP-43) or RNA-binding protein fused in sarcoma (FUS). Therefore, lcn2 is induced in activated astrocytes in response to neurodegeneration, but its induction is independent of TDP-43 or FUS expression in astrocytes. We found that synthetic lcn2 is cytotoxic to primary neurons in a dose-dependent manner, but is innocuous to astrocytes, microglia, and oligodendrocytes. Lcn2 toxicity is increased in neurons that express a disease gene, such as mutant FUS or TDP-43. Conditioned medium from rat brain slice cultures with neuronal expression of mutant TDP-43 contains abundant lcn2 and is toxic to primary neurons as well as neurons in cultured brain slice from WT rats. Partial depletion of lcn2 by immunoprecipitation reduced conditioned medium-mediated neurotoxicity. Our data indicate that reactive astrocytes secrete lcn2, which is a potent neurotoxic mediator.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 110 (10), 4069-4074, 2013-02-19
Proceedings of the National Academy of Sciences
