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Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, de Luis A, Neukomm LJ, Cabello J, Farese RV, Kenyon C. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4441-6. PubMed.
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Boston University School of Medicine
This is a very interesting study by Cynthia Kenyon's team. Their work in nematodes convincingly provides clear demonstration of a role for progranulin in phagocytosis, and confirms it by abrogation of the effect of progranulin deletion by deletion of other genes in the phagocytic pathway. The work with mouse macrophages provides useful translation to the mammalian context. A weakness in the C. elegans study is the inability to fully genetically complement the deletion of progranulin by expressing the progranulin gene transgenically. Kenyon's team suggests that this is likely due to differences in gene expression between endogenous and expressed genes. This explanation is probably correct; however, it is also possible that the incomplete complementation results from mutations at other sites in the nematode genome that might impact on phagocytosis.
The team's discovery that progranulin insufficiency increases phagocytosis is a surprise, because we have come to associate neurodegeneration with reduced catabolic activity, rather than an increase in degradative processes. Kenyon proposes that the increased phagocytosis that might be associated with frontotemporal dementia (FTD) is the cause of the illness. I think this hypothesis is premature because progranulin is expressed in many cell types and exerts many different actions. The role in phagocytosis is quite believable and probably true, but jumping from there to proposing that this is the cause of FTD is too large of a leap. However, the proposal does suggest experiments that are relatively straightforward to test, such as the conditional knockout of progranulin gene in the macrophage lineage. Regardless, this is a provocative and interesting study that definitely moves the field forward.
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