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© The Rockefeller University Press, 0021-9525/1998//1313 $5.00
The Journal of Cell Biology, Volume 142, Number 5, , 1998 1313-1324

Articles

Control of Neuronal Size Homeostasis by Trophic Factor–mediated Coupling of Protein Degradation to Protein Synthesis



James L. Franklin* and Eugene M. Johnson, Jr.{ddagger}

* Department of Neurological Surgery, 4640 MSC, University of Wisconsin School of Medicine, Madison, Wisconsin 53706; and {ddagger} Department of Neurology and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

We demonstrate that NGF couples the rate of degradation of long-lived proteins in sympathetic neurons to the rate of protein synthesis. Inhibiting protein synthesis rate by a specific percentage caused an almost equivalent percentage reduction in the degradation rate of long-lived proteins, indicating nearly 1:1 coupling between the two processes. The rate of degradation of short-lived proteins was unaffected by suppressing protein synthesis. Included in the pool of proteins that had increased half-lives when protein synthesis was inhibited were actin and tubulin. Both of these proteins, which had half-lives of several days, exhibited no degradation over a 3-d period when protein synthesis was completely suppressed. The half-lives of seven other long-lived proteins were quantified and found to increase by 84–225% when protein synthesis was completely blocked.

Degradation–synthesis coupling protected cells from protein loss during periods of decreased synthesis. The rate of protein synthesis greatly decreased and coupling between degradation and synthesis was lost after removal of NGF. Uncoupling resulted in net loss of cellular protein and somatic atrophy. We propose that coupling the rate of protein degradation to that of protein synthesis is a fundamental mechanism by which neurotrophic factors maintain homeostatic control of neuronal size and perhaps growth.

Key Words: protein turnover • sympathetic neuron • growth • caspase • nerve growth factor

Abbreviations used in this paper: ACT D, actinomycin D; ANIS, anisomycin; BAF, Boc-aspartyl (OMe)-fluromethyl ketone; CHX, cycloheximide; SCG, superior cervical ganglion.

Address all correspondence to James L. Franklin, Department of Neurological Surgery, 4640 MSC, 1300 University Avenue, University of Wisconsin School of Medicine, Madison, WI 53706. Tel.: (608) 263-5468. Fax: (608) 265-3461. E-mail: jlfrankl{at}facstaff.wisc.edu

Portions of this work have appeared in abstract form (Franklin, J.L., and E.M. Johnson, Jr. 1995. NGF couples protein synthesis and degradation in sympathetic neurons. Soc. Neurosci. Abstr. 21:1050).


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