Proteasome inhibition arrests neurite outgrowth and causes "dying-back" degeneration in primary culture.
Proteasome inhibitors such as lactacystin were first isolated when assaying their ability to stimulate neurite outgrowth in neuronal-like cell lines; however, their effect on neurites in primary culture has been largely neglected. We report here that lactacystin causes immediate arrest of nerve growth factor (NGF)-stimulated neurite outgrowth in sympathetic and sensory explant cultures. This is followed by neurite degeneration that in sympathetic cultures has a distinctive "dying-back" morphology. Remarkably, this occurs even at concentrations below that required to induce neurite outgrowth in PC12 cells. Thus, lactacystin opposes rather than potentiates the effect of NGF on sympathetic neurite outgrowth and the role of the ubiquitin proteasome pathway in growth and long-term maintenance of axons and dendrites differs from that in neuritogenesis in neuronal-like cell lines. Retrograde degeneration caused by blocking of the ubiquitin proteasome pathway may mimic some aspects of gracile axonal dystrophy, a dying-back axonopathy in mice caused by ubiquitin hydrolase (Uch-l1) deficiency, and may be relevant to human neurodegenerative diseases involving ubiquitination or proteasome abnormalities.
Laser
Heike
H
Institute for Genetics and ZMMK, Cologne, Germany.
Mack
Till G A
TG
Wagner
Diana
D
Coleman
Michael P
MP
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology*; D009433:Neural Inhibition / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex; D051381:Rats
D006131:Growth Inhibitors; D009097:Multienzyme Complexes; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine