Lovastatin induces the formation of abnormal myelin-like membrane sheets in primary oligodendrocytes.
Statins, well-known inhibitors of cholesterol synthesis and protein isoprenylation, have been proposed as therapeutic drugs for multiple sclerosis (MS). As lovastatin and simvastatin, which are currently tested for their use in MS, can cross the blood-brain barrier, they may affect cellular processes in the central nervous system. This is especially relevant with respect to remyelination as a proposed additional treatment for MS, because cholesterol is a major component of myelin. Here, we show that primary oligodendrocytes, treated with lovastatin, form extensive membrane sheets, which contain galactosphingolipids. However, these membrane sheets are devoid of the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP). Reduced MBP protein expression was confirmed by SDS-PAGE and Western blotting, and in situ hybridization experiments revealed that lovastatin blocks MBP mRNA transport into oligodendrocyte processes. In contrast, PLP expression was only mildly affected by lovastatin. However, lovastatin treatment resulted in intracellular accumulation of PLP and prevented its translocation to the cell surface. Interestingly, another inhibitor of cholesterol synthesis (ro48-8071), which does not interfere with isoprenylation, had a similar effect on the localization of PLP, but it did not affect MBP expression and localization. These results suggest that lovastatin affects PLP transport predominantly by the inhibition of cholesterol synthesis, whereas reduced MBP expression is caused by impaired isoprenylation. Based on these results we recommend to carefully monitor the effect of statins on myelination prior to their use in demyelinating diseases.
Maier
Olaf
O
Section of Membrane Cell Biology, Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. olaf.maier@izi.uni-stuttgart.de
De Jonge
Jenny
J
Nomden
Anita
A
Hoekstra
Dick
D
Baron
Wia
W
D000818:Animals; D000831:Animals, Newborn; D001577:Benzophenones / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects; D010710:Phosphates / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D001577:Benzophenones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018991:Myelin Proteolipid Protein; D010710:Phosphates; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; C105726:Ro 48-8071; D002784:Cholesterol; D008148:Lovastatin; C002963:geranylgeranyl pyrophosphate