Roles for PMP22 in Schwann cell cholesterol homeostasis in health and disease

Abstract

Underexpression, overexpression, and point mutations in peripheral myelin protein 22 (PMP22) cause most cases of Charcot-Marie-Tooth disease (CMTD). While its exact functions remain unclear, PMP22 is clearly essential for formation and maintenance of healthy myelin in the peripheral nervous system. This review explores emerging evidence for roles of PMP22 in cholesterol homeostasis. First, we highlight dysregulation of lipid metabolism in PMP22-based forms of CMTD and recently-discovered interactions between PMP22 and cholesterol biosynthesis machinery. We then examine data that demonstrates PMP22 and cholesterol co-traffic in cells and co-localize in lipid rafts, including how disease-causing PMP22 mutations result in aberrations in cholesterol localization. Finally, we examine roles for interactions between PMP22 and ABCA1 in cholesterol efflux. Together, this emerging body of evidence suggests that PMP22 plays a role in facilitating enhanced cholesterol synthesis and trafficking necessary for production and maintenance of healthy myelin.

Keywords: Charcot-Marie-Tooth disease; PMP22; cholesterol; myelin; peripheral myelin protein 22; peripheral nervous system.

Figure 1.. Cartoon representation for the AlphaFold2-predicted structure of PMP22.

Highlighted are locations of the CRAC motif in TM4 (residues 147–159, red), CARC motif in TM3 (residues 92–104, blue), and palmitoylation site (residue C85, yellow sticks). CRAC and CARC motifs are often observed in cholesterol-binding sites. Conserved tyrosine residues within these sites are known to be critical for cholesterol binding. Palmitoylation site C85 and CRAC/CARC residues Y97 and Y153 are represented by stick models.

Figure 2.. PMP22, cholesterol biosynthesis and cholesterol trafficking.

(A) Schematic of cholesterol biosynthesis pathway in the endoplasmic reticulum highlighting PMP22 interactors EMC4, PGRMC1, DHCR7 and DHCR24 as identified by proteomics. (B) Trafficking of newly synthesized cholesterol in Schwann cells. Typical pathways for cholesterol from ER to PM shown with blue arrows (thick arrow = major pathway, thin arrows = minor pathway). Major sites of cholesterol accumulation under different PMP22 genetic backgrounds shown.