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. doi: 10.1073/pnas.1100650108. Epub 2011 Feb 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / embryology
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / metabolism
  • Granulins
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / cytology
  • Kinetics
  • Longevity
  • Macrophages / cytology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Mutation / genetics*
  • Neurodegenerative Diseases / genetics*
  • Neurons / cytology
  • Neurons / metabolism
  • Phagocytosis

Substances

  • Apoptosis Regulatory Proteins
  • Caenorhabditis elegans Proteins
  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins