Lovastatin induces the formation of abnormal myelin‐like membrane sheets in primary oligodendrocytes

Abstract

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.

Mutation of 3-Hydroxy-3-Methylglutaryl CoA Synthase I Reveals Requirements for Isoprenoid and Cholesterol Synthesis in Oligodendrocyte Migration Arrest, Axon Wrapping, and Myelin Gene Expression

“…Although white matter abnormalities have been noted in some SLOS patients (Lee et al, 2013), the nature of the defect is not understood nor is it clear whether it results from a deficit of cholesterol or an increase in its precursor, 7-dehydrocholesterol. Statins interfere with oligodendrocyte differentiation, myelination, and remyelination in cell culture and rodent models (Klopfleisch et al, 2008;Maier et al, 2009;Miron et al, 2009;Smolders et al, 2010), but whether these defects result from deficits of isoprenoids, cholesterol, or both has not been known. By establishing that different features of oligodendrocyte development have distinct requirements for isoprenoids and cholesterol, our work should help clarify the brain abnormalities resulting from sterol metabolism defects and illuminate specific risks associated with statin therapy.…”

“…Sequencing of cDNA obtained from vu57 mutant larvae revealed a T to A transversion predicted to change histidine to glutamine at amino acid position 189 (H189Q, GenBank accession NP_ 957379; Fig. 3A) within a homodimerization domain identified by the Conserved Domain Database (Marchler-Bauer et al, 2013). Total cholesterol was reduced ϳ50% in 4 dpf vu57 mutant larvae relative to wild-type larvae (n ϭ 3 biological replicates consisting of 20 -30 larvae per sample; p Ͻ 0.05, unpaired parametric t test), consistent with the possibility that the vu57 mutant allele disrupts Hmg-CoA synthase 1 function and diminishes cholesterol synthesis.…”

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

“…Remarkably, statins can ameliorate remyelination in an animal model of multiple sclerosis (MS) (140)(141)(142)(143), possibly via augmenting survival and differentiation of oligodendrocyte progenitors, and therefore have been tested in MS trials ( 144,145 ). However, statins induce the formation of abnormal myelin-like membrane sheets in primary oligodendrocytes in vitro, due to impairment of cholesteroldependent myelin protein transport ( 146 ), which indicates a risk of the use of statins for myelin membrane integrity. In addition, statins are reported to increase the risk of developing peripheral neuropathy ( 147 ), although there is some controversy concerning the exact amplitude of this risk, which furthermore appeared to be reversible and will need further study ( 148,149 ).…”

Controlling immune response and demyelination using highly potent bifunctional peptide inhibitors in the suppression of experimental autoimmune encephalomyelitis

“…Maier et al reported that, although lovastatin promoted the formation of membrane sheets by primary oligodendrocytes (OLGs), the membranes lacked major myelin proteins (e.g. MBP and PLP) and showed an abnormal microtubule cytoskeleton [47]. Although lovastatin could be a potential agent for the treatment of MS, it might be a good idea to conduct extended studies on its effects in the CNS, particularly in the targeted patient population.…”