PCSK9 deficiency promotes the development of peripheral neuropathy

PCSK9 is a serine protease primarily produced and secreted by the liver. Its best-known and studied function is to induce the hepatic degradation of the low-density lipoprotein (LDL) receptor (LDLR), thereby increasing the concentration of LDL-cholesterol (LDL-C) in the blood. Beyond its effects on LDL-C metabolism, recent studies have reported pleiotropic biological roles for PCSK9 notably in septic shock, vascular inflammation, viral infection, and cancer. While the function and the structural integrity of peripheral nerves are critically influenced by circulating lipids and cholesterol levels, the impact of PCSK9 in the peripheral nervous system is still unexplored. In this study, we investigated the consequences of PCSK9 deficiency on the physiology of peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy characterized by a reduction of 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 through its impact on CD36, PCSK9 deficiency could lead to the development of symptoms related to peripheral neuropathy.