Molecular and cellular mechanism of neuronal degeneration caused by nerve growth factor deprivation approached through PC12 cell culture.

1. Degenerative processes of PC12 cells after acute withdrawal of nerve growth factor (NGF) were characterized. PC12 cells treated with NGF share properties similar to sympathetic neurons, and only these cells responded to acute withdrawal of NGF by degeneration characterized by disappearance of growth cones, neurite disintegration, and eventually cell death. 2. The cell pool of ATP and release of lactate dehydrogenase (LDH) into medium were measured and taken as a quantitative measure of cell degeneration. 3. The release of LDH after NGF withdrawal was not completely blocked by cycloheximide or cordycepin, suggesting that active cell death occurred only partially in PC12 cells. Degeneration processes including neurite disintegration did not require protein synthesis. All the degenerative processes were completely prevented by chronic depolarization with high K+ and cyclic AMP. 4. Preliminary evidence was presented on a transient induction of the proto-oncogene c-fos upon acute withdrawal of NGF. Thus, one of the interesting aspects available from studies of PC12 cells would be to compare pathways initiated by NGF deprivation to those activated by NGF exposure to naive PC12 cells, since the latter pathways have been extensively studied. 5. These results suggest that PC12 cells serve as a model system for studying neuronal degeneration caused by acute withdrawal of NGF. We also suggest that NGF removal elicits divergent cellular signalling pathways leading to cell degeneration, some of which may be utilized in common with those activated by NGF exposure to naive PC12 cells.