NEUROPATHOLOGY OF DEGENERATIVE CELL-DEATH IN CAENORHABDITIS-ELEGANS

In Caenorhabditis elegans necrosis-like neuronal death is induced by g ain-of-function (gf) mutations in two genes, mec-4 and deg-1, that enc ode proteins similar to subunits of the vertebrate amiloride-sensitive epithelial Na+ channel. We have determined the progress of cellular p athology 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 vacuole s and larger membranous whorls form, and the cell swells. More slowly, chromatin aggregates and the nucleus invaginates. Mitochondria and Go lgi are not dramatically affected until the final stages of cell death when organelles, and sometimes the cells themselves, lyse. Certain ce lls, including some muscle cells in deg-1 animals, express the abnorma l gene products and display a few membrane abnormalities but do not di e. These cells either express the mutant genes at lower levels, lack o ther proteins needed to form inappropriately functioning channels, or are better able to compensate for the toxic effects of the channels. O verall, the ultrastructural changes in these deaths suggest that enhan ced membrane cycling precedes vacuolation and cell swelling. The patho logy of mec-4(gf) and deg-1(gf) cells shares features with that of gen etic disorders with alterations in channel subunits, such as hypokalem ic periodic paralysis in humans and the weaver mouse, and with degener ative 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.