EFFECTS OF A DECREASE IN THE PROTEASOME ACTIVITY ON MYELINATION

PASQUINI, L.A., MILLET, V., MOIOLA, C.P., SOTO, E.F., PASQUINI, J.M.

Innsruck, Austria

Congreso; 20th biennial Meeting of the International Society for Neurochemistry and the European Society for Neurochemistry; 2005

International Society for Neurochemistry and the European Society for Neurochemistry

We have demonstrated that addition of low concentrations of lactacystin to OLGc cultures induces their exit from the cell cycle and their differentiation. We evaluated the in vivo effects on myelinationremyelination of a decrease in proteasome activity. Mice were intracranially injected (ICI) in corpus callosum with lactacystin at day P5 and P7 and evaluated at day 15 (protocol 1). On other hand, mice undergoing a spontaneous remyelination after cuprizone-induced demyelination, were similarly injected with lactacystin at day 5 of their remyelination period and evaluated 10 days after the injection (protocol 2). Lactacystin ICI in mice significantly decreases proteasome activities in the brain. In animals (protocol 1) lactacystin ICI induced a increase in the values of myelin protein and of myelin cerebroside content (P < 0.001), a higher immunoreactivity to O1 and a decrease in the mRNA of Sp1, an increase in the mRNA of different isoforms of MBP, an increase in the levels of expression of PDGF receptor and a decrease in the expression of GFAP. In animals (protocol 2) the lactacystin ICI induced a marked increase in myelin deposition, a significant increase in the values of proteins and galactolipids in purified myelin, a significant increase in the expression of the different isoforms of MBP and of the PDGF receptor and of GFAP in comparison to spontaneous recovering animals. We have also found that in OLGcs primary cultures, lactacystin stabilizes the proliferation signals (PDGF+bFGF) with a significant increase in S phase cells. These results seem indicate that the decrease in proteasome activity stabilizes proliferation/differentiation signals coming from the cell surrounding.