Neuropathology of degenerative cell death in Caenorhabditis elegans.
In Caenorhabditis elegans necrosis-like neuronal death is induced by gain-of-function (gf) mutations in two genes, mec-4 and deg-1, that encode proteins similar to subunits of the vertebrate amiloride-sensitive epithelial Na+ channel. We have determined the progress of cellular pathology in dying neurons via light and electron microscopy. The first detectable abnormality is an infolding of the plasma membrane and the production of small electron-dense whorls. Later, cytoplasmic vacuoles and larger membranous whorls form, and the cell swells. More slowly, chromatin aggregates and the nucleus invaginates. Mitochondria and Golgi are not dramatically affected until the final stages of cell death when organelles, and sometimes the cells themselves, lyse. Certain cells, including some muscle cells in deg-1 animals, express the abnormal gene products and display a few membrane abnormalities but do not die. These cells either express the mutant genes at lower levels, lack other proteins needed to form inappropriately functioning channels, or are better able to compensate for the toxic effects of the channels. Overall, the ultrastructural changes in these deaths suggest that enhanced membrane cycling precedes vacuolation and cell swelling. The pathology of mec-4(gf) and deg-1(gf) cells shares features with that of genetic disorders with alterations in channel subunits, such as hypokalemic periodic paralysis in humans and the weaver mouse, and with degenerative conditions, e.g., acute excitotoxic death. The initial pathology in all of these conditions may reflect attempts by affected cells to compensate for abnormal membrane proteins or functions.
Hall
D H
DH
Department of Neurosciences, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Gu
G
G
García-Añoveros
J
J
Gong
L
L
Chalfie
M
M
Driscoll
M
M
D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology*; D029742:Caenorhabditis elegans Proteins; D016923:Cell Death; D018628:Gene Dosage; D017238:Genes, Helminth / Q000502:physiology*; D015801:Helminth Proteins / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure
D029742:Caenorhabditis elegans Proteins; C094927:Deg-1 protein, C elegans; D015801:Helminth Proteins; D008565:Membrane Proteins