A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells
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- Aimee W. Kao
- Departments of aBiochemistry and Biophysics and
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- Robin J. Eisenhut
- Departments of aBiochemistry and Biophysics and
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- Lauren Herl Martens
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158;
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- Ayumi Nakamura
- Departments of aBiochemistry and Biophysics and
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- Anne Huang
- Departments of aBiochemistry and Biophysics and
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- Josh A. Bagley
- Departments of aBiochemistry and Biophysics and
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- Ping Zhou
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158;
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- Alberto de Luis
- Center for Biomedical Research of La Rioja, 26006 Logrono, Spain;
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- Lukas J. Neukomm
- Institute of Molecular Life Sciences, University of Zurich, CH8057 Zurich, Switzerland; and
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- Juan Cabello
- Center for Biomedical Research of La Rioja, 26006 Logrono, Spain;
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- Robert V. Farese
- Departments of aBiochemistry and Biophysics and
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- Cynthia Kenyon
- Departments of aBiochemistry and Biophysics and
抄録
<jats:p>Frontotemporal lobar degeneration is a progressive neurodegenerative syndrome that is the second most common cause of early-onset dementia. Mutations in the progranulin gene are a major cause of familial frontotemporal lobar degeneration [Baker M, et al. (2006)<jats:italic>Nature</jats:italic>442:916–919 and Cruts M, et al. (2006)<jats:italic>Nature</jats:italic>442:920–924]. Although progranulin is involved in wound healing, inflammation, and tumor growth, its role in the nervous system and the mechanism by which insufficient levels result in neurodegeneration are poorly understood [Eriksen and Mackenzie (2008)<jats:italic>J Neurochem</jats:italic>104:287–297]. We have characterized the normal function of progranulin in the nematode<jats:italic>Caenorhabditis elegans.</jats:italic>We found that mutants lacking<jats:italic>pgrn-1</jats:italic>appear grossly normal, but exhibit fewer apoptotic cell corpses during development. This reduction in corpse number is not caused by reduced apoptosis, but instead by more rapid clearance of dying cells. Likewise, we found that macrophages cultured from progranulin KO mice displayed enhanced rates of apoptotic-cell phagocytosis. Although most neurodegenerative diseases are thought to be caused by the toxic effects of aggregated proteins, our findings suggest that susceptibility to neurodegeneration may be increased by a change in the kinetics of programmed cell death. We propose that cells that might otherwise recover from damage or injury are destroyed in progranulin mutants, which in turn facilitates disease progression.</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 108 (11), 4441-4446, 2011-02-28
Proceedings of the National Academy of Sciences