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Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet
Gesine Saher1, Fabian Rudolphi1,3, Kristina Corthals1,3, Torben Ruhwedel1, Karl-Friedrich Schmidt2, Siegrid Lwel2, Payam Dibaj1, Benoit Barrette1, Wiebke Mbius1 & Klaus-Armin Nave1
npg 2012 Nature America, Inc. All rights reserved.
Duplication of PLP1 (proteolipid protein gene 1) and the subsequent overexpression of the myelin protein PLP (also known as DM20) in oligodendrocytes is the most frequent cause of Pelizaeus-Merzbacher disease (PMD), a fatal leukodystrophy1 without therapeutic options2,3. PLP binds cholesterol and is contained within membrane lipid raft microdomains4. Cholesterol availability is the rate-limiting factor of central nervous system myelin synthesis5. Transgenic mice with extra copies of the Plp1 gene6 are accurate modelsof PMD. Dysmyelination68 followed by demyelination9,10, secondary inflammation and axon damage contributeto the severe motor impairment in these mice9,10. Thefinding that in Plp1-transgenic oligodendrocytes, PLP and cholesterol accumulate in late endosomes and lysosomes (endo/lysosomes)9,1113, prompted us to further investigatethe role of cholesterol in PMD. Here we show that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology. In a preclinical trial, PMD mice were fed a cholesterol-enriched diet. This restored oligodendrocyte numbers and ameliorated intracellularPLP accumulation. Moreover, myelin content increased, inflammation and gliosis were reduced and motor defects improved. Even after onset of clinical symptoms, cholesterol treatment prevented disease progression. Dietary cholesterol did not reduce Plp1 overexpression but facilitated incorporation of PLP into myelin membranes. These findings may have implications for therapeutic interventions in patients with PMD.
We have previously shown that mouse mutants lacking cholesterol synthesis in oligodendrocytes (Fdft1flox/flox Cnp1+/cre, termed
cSQS knockout) express myelin protein genes, including Plp1, at a low level5. We therefore tested the potential application of an inhibitor of squalene synthase and cholesterol synthesis (squalestatin) for the downregulation of toxic Plp1 overexpression in mice with increased Plp1 gene dosage6 (PLP-tg72/72, Plp1 transgenic line 72 containing three copies of the transgene, termed PMD mice hereafter, Supplementary Table 1). To protect PMD mice from the possible side effects of high-dose squalestatin treatment, we supplemented
peripheral cholesterol levels with a high-cholesterol diet. We assumed that the CNS was shielded from cholesterol from the circulation by the blood-brain barrier (BBB)14. To our surprise, all mice of this pilot trial improved dramatically...