The importance of lipids in regulating OL responses is highlighted by the dysregulation of their synthesis or transport in neurological disorders characterized by OL injury and dysfunction. For instance, the cholesterol biosynthesis pathway is downregulated in MS and in astrocytes in the poorly remyelinating model EAE119, and single nuclei sequencing of chronic active MS lesions indicate altered lipid storage/response genes in microglia and astrocytes47. Decreased cholesterol levels observed in Smith-Lemli-Optiz Syndrome (SLOS) due to 7-dehydrocholesterol reductase (DHCR7) dysfunction are associated with abnormal developmental myelination120,121. Conversely, cholesterol accumulation can lead to hypomyelination and decompacted myelin as observed in some leukodystrophies. For instance, Pelizaeus-Merbacher disease is caused by a mutation in the myelin gene PLP1, which results in the accumulation of cholesterol and membrane raft components in lysosomal compartments due to mistrafficking of these myelin elements122–125. In addition, in Niemann-Pick disease type C, caused by mutations in regulators of cholesterol transport NPC1 or NPC2, results in cholesterol accumulated in the lysosomes126–128. Cholesterol accumulation can also lead to demyelination, as seen in Cerebrotendinous Xanthomatosis, caused by mutations in the sterol 27-hydroxylase gene (CYP27A1)129,130.
