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Proteasome inhibition arrests neurite outgrowth and causes “dying‐back” degeneration in primary culture
Author(s) -
Laser Heike,
Mack Till G.A.,
Wagner Diana,
Coleman Michael P.
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10806
Subject(s) - neurite , lactacystin , proteasome , microbiology and biotechnology , nerve growth factor , ubiquitin , cell culture , biology , neuroscience , proteasome inhibitor , in vitro , biochemistry , genetics , receptor , gene
Abstract 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. © 2003 Wiley‐Liss, Inc.