RRC ID 46618
Author Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, de Luis A, Neukomm LJ, Cabello J, Farese RV Jr, Kenyon C.
Title A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells.
Journal Proc. Natl. Acad. Sci. U.S.A.
Abstract 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) Nature 442:916-919 and Cruts M, et al. (2006) Nature 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) J Neurochem 104:287-297]. We have characterized the normal function of progranulin in the nematode Caenorhabditis elegans. We found that mutants lacking pgrn-1 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.
Volume 108(11)
Pages 4441-6
Published 2011-3-15
DOI 10.1073/pnas.1100650108
PII 1100650108
PMID 21368173
PMC PMC3060230
MeSH Animals Apoptosis / genetics* Apoptosis Regulatory Proteins / genetics* Apoptosis Regulatory Proteins / secretion Caenorhabditis elegans / cytology Caenorhabditis elegans / embryology Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / secretion Embryo, Nonmammalian / cytology Embryo, Nonmammalian / metabolism Intercellular Signaling Peptides and Proteins / genetics* Intercellular Signaling Peptides and Proteins / metabolism Intestines / cytology Intestines / metabolism Kinetics Longevity Macrophages / cytology Macrophages / metabolism Mice Mice, Knockout Models, Biological Mutation / genetics* Neurodegenerative Diseases / genetics* Neurons / cytology Neurons / secretion Phagocytosis
IF 9.504
Times Cited 51
WOS Category NEUROSCIENCES
Resource
C.elegans tm985