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Constitutively expressed catalytic proteasomal subunits are up‐regulated during neuronal differentiation and required for axon initiation, elongation and maintenance
Author(s) -
Klimaschewski Lars,
Hausott Barbara,
Ingorokva Shota,
Pfaller Kristian
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03694.x
Subject(s) - neurite , lactacystin , proteasome , axon , microbiology and biotechnology , protein subunit , biology , neurofilament , neuron , neuroscience , in vitro , biochemistry , proteasome inhibitor , immunology , immunohistochemistry , gene
Inhibition of the proteasome by lactacystin, a specific blocker of the catalytic β‐subunits, results in transient neurite outgrowth by neuronal cell lines. Vice versa, as demonstrated in this study, treatment of pheochromocytoma (PC12) cells with nerve growth factor (NGF) or other differentiating agents reduces proteasomal activity. This is accompanied by an increase in mRNA and protein levels of the catalytically active subunits β1, β2 and β5, but not of their inducible counterparts, indicating changes in subunit composition of the proteasome during neuronal differentiation. In contrast to neuronal cell lines, however, pre‐treatment of primary neurons with proteasome inhibitors completely prevents axon formation, and lower concentrations of lactacystin (0.5–5 µ m ) significantly reduce axonal elongation and branching in vitro . Furthermore, established axonal networks degenerate rapidly and long‐term survival of peripheral neurons is impaired in the presence of proteasome inhibitors. Axonal pathology is reminiscent of the morphological changes observed in neurodegenerative disorders and supports a crucial role of the constitutive catalytic subunits in axon initiation, maintenance and regeneration.