Fig. 2.

Leukodystrophy-associated proteins in microglia. Several microglial proteins, either at the cell surface or residing within organelles, are involved in leukodystrophy-related cellular processes. CSF1R is a dimeric transmembrane receptor that is a key regulator of microglia and macrophage biology, including proliferation, migration and survival, and binds ligands CSF-1 and IL-34. TREM2 is a single-pass transmembrane receptor involved in lipid metabolism and phagocytic clearance by macrophages and microglia. It binds anionic ligands, including phospholipids and bacterial components, and forms a signaling complex with DAP12, which is a dimeric transmembrane adapter required for the cell-surface expression of TREM2, forming a signaling complex. LRRC33 is a leucine-rich repeat-containing protein that anchors latent TGF-β1 at the cell surface. It is required for activation of the TGF-β1 pathway in macrophages and microglia. The USP18 isopeptidase binds to the intracellular domain of IFNAR2, thereby negatively regulating the IFN-I pathway. ALDP, a peroxisomal ABC half-transporter encoded by ABCD1, transports VLCFAs. ASA, encoded by ARSA, is a lysosomal enzyme that digests sulfatides, glycosphingolipids that are highly enriched in myelin. GALC, encoded by GALC, is a lysosomal enzyme catabolizing galactosylceramide and psychosine, both major glycosphingolipids in myelin. ASA and GALC are not known to be expressed at high levels in macrophages and microglia, but there are strong indications that their functions are required by microglia in the context of myelin.