CONTROL OF NEURONAL SIZE HOMEOSTASIS BY TROPHIC FACTOR-MEDIATED COUPLING OF PROTEIN-DEGRADATION TO PROTEIN-SYNTHESIS

We demonstrate that NGF couples the rate of degradation of long-lived proteins in sympathetic neurons to the rate of protein synthesis. Inhi biting protein synthesis rate by a specific percentage caused an almos t equivalent percentage reduction in the degradation rate of long-live d proteins, indicating nearly 1:1 coupling between the two processes. The rate of degradation of short-lived proteins was unaffected by supp ressing protein synthesis. Included in the pool of proteins that had i ncreased half-lives when protein synthesis was inhibited were actin an d tubulin, Both of these proteins? which had half-lives of several day s, exhibited no degradation over a 3-d period when protein synthesis w as completely suppressed. The half-lives of seven other long-lived pro teins were quantified and found to increase by 84-225 % when protein s ynthesis was completely blocked. Degradation-synthesis coupling protec ted cells from protein loss during periods of decreased synthesis. The rate of protein synthesis greatly decreased and coupling between degr adation and synthesis was lost after removal of NGF. Uncoupling result ed in net loss of cellular protein and somatic atrophy. We propose tha t coupling the rate of protein degradation to that of protein synthesi s is a fundamental mechanism by which neurotrophic factors maintain ho meostatic control of neuronal size and perhaps growth.