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The Journal of Neuroscience, June 1, 2003, 23(11):4635-4644

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Inhibition of the Proteasome by Lactacystin Enhances Oligodendroglial Cell Differentiation

Laura A. Pasquini, Pablo M. Paez, Marcos A. N. Besio Moreno, Juana M. Pasquini, and Eduardo F. Soto

Departamento de Química Biológica, Instituto de Química y Fisicoquímica Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1113, Argentina

We have used lactacystin, a specific inhibitor of the 26S proteasome, in oligodendroglial cell (OLGc) primary cultures to explore the possible participation of the proteasome–ubiquitin-dependent pathway in the decision of the OLGcs to arrest their proliferation and start differentiation. Addition of lactacystin at various concentrations to cultures containing a majority of OLGc was found to produce their withdrawal from the cell cycle and to induce their biochemical and morphological differentiation, with the appearance of extensive myelin-like sheets. The three classic proteolytic activities of the proteasome were significantly decreased in the lactacystin-treated cultures, and the immunocytochemical analysis showed an increase in the number of O4-, O1-, myelin basic protein-, and myelin proteolipid protein-positive cells and a decrease in A2B5-reacting cells. Quantitative immunochemical evaluation of the expression of certain proteins controlling the cell cycle showed an increase in p27^kip1-, cyclin D-, and cdk4-positive cells, with a decrease in cyclin E- and cdk2-positive cells. In the lactacystin-treated OLGcs, there was a dose-dependent decrease in the number of cells incorporating bromodeoxyuridine and in the activity of the complexes cyclin D–cdk4 and cyclin E–cdk2. Furthermore, increased levels of expression of several STAT factors were found, suggesting that proteasome inhibition in OLGcs could stabilize signals of survival and differentiation that might be processed through the JAK/STAT signaling cascade.

Key words: oligodendroglial cells; lactacystin; MG132; differentiation; cyclins; p27^kip1; JAK/STAT; ubiquitin; proteasome; myelination

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Received Aug. 26, 2002; revised Mar. 12, 2003; accepted Mar. 19, 2003.

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