PCSK9 deficiency promotes the development of peripheral neuropathy

PCSK9 best-known and studied function is to induce the hepatic degradation of the low-density lipoprotein receptor (LDLR), thereby increasing the concentration of LDL-cholesterol (LDL-C) in the blood. Beyond its effects on LDL, recent studies have reported pleiotropic effects of PCSK9 notably in septic shock, vascular inflammation, viral infection, and cancer. While the functional and structural integrity of peripheral nerves are critically influenced by circulating lipids, the impact of PCSK9 in the peripheral nervous system is unknown. In this study, we investigated the consequences of PCSK9 deficiency on peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy characterized by a reduction of thermal and mechanical pain sensations. PCSK9 deficient mice also presented skin structural changes with a reduction of number of terminal nociceptive Schwann cells, Remak fiber axonal swelling, as well as hypomyelination of small nerve fibers. Interestingly, peripheral nerves of PCSK9 deficient mice presented an upregulation of the fatty acid transporter CD36 expression which correlated with an increase in nerve lipid contents and structural mitochondrial abnormalities. Our findings demonstrate that PCSK9 plays a critical role in the peripheral nerves by regulating lipid homeostasis, and its deficiency could lead to the development of symptoms related to peripheral neuropathy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/583154v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1469ef8org.highwire.dtl.DTLVardef@16ebcd9org.highwire.dtl.DTLVardef@1305cbborg.highwire.dtl.DTLVardef@181758_HPS_FORMAT_FIGEXP M_FIG C_FIG PCSK9 modulates nerve energy metabolism and health. Created with BioRender.com.