NARCO

PCSK9 is a circulating protein primarily synthesized by the liver. It inhibits the expression of the LDL receptor (LDLR), and thereby elevates LDL-cholesterol (LDL-C) levels in the plasma. PCSK9 inhibitors are currently used on top of statins to lower circulating LDL-C concentrations and reduce the associated cardiovascular risk. Peripheral nerve function is critically influenced by their lipid composition as well as by the concentration of cholesterol in the circulation. Despite its initial identification in the nervous system and its central role in modulating plasma lipids, the role of PCSK9 in the peripheral nervous system is still unknown. The aims of the current proposal are to elucidate the pathophysiological mechanisms by which PCSK9 deficiency induces a neuropathic phenotype characterized by a loss in pain sensation associated with abnormalities of lipid metabolism in peripheral nerves. This proposal stems from key results of our recent study conducted in PCSK9 deficient mice (PCSK9 KO). We will specifically investigate whether the neuropathic phenotype of PCSK9 KO mice is a direct consequence of the lack of PCSK9 locally expressed by sensory neurons or Schwann cells or alternatively whether it results from the absence of circulating PCSK9 and associated perturbations of lipoprotein metabolism, using a series of mouse models genetically engineered to lack PCSK9 specifically in sensory neurons, Schwann cells or in the liver. We will also evaluate the effects of inhibiting the circulating form of PCSK9 on the peripheral nervous system using pharmacological inhibitors of this protein in a mouse model of diabetic neuropathy. We will finally ascertain our experimental results epidemiologically by undertaking a comprehensive study of a large human cohort. The combined results of this study will unravel key aspects of PCSK9 biology in the peripheral nervous system and assess the effects of its modulation on diabetic peripheral neuropathy.