"LA DÉFICIENCE EN PCSK9 PROVOQUE UNE NEUROPATHIE PÉRIPHÉRIQUE CHEZ LA SOURIS, LIÉE À UNE ACCUMULATION TOXIQUE DE LIPIDES DANS LES NERFS, RÉVÉLANT UN RÔLE INATTENDU DE CETTE PROTÉINE DANS LA SANTÉ NEURONALE."
L'étude menée par l'équipe de Steeve Bourane, chercheur à DéTROI révèle que la déficience en PCSK9 favorise le développement d’une neuropathie périphérique chez la souris. La PCSK9, connue pour réguler le cholestérol LDL, jouerait également un rôle crucial dans le système nerveux périphérique. Les souris dépourvues de PCSK9 présentent une hypersensibilité réduite à la douleur, des anomalies structurales (comme une diminution des cellules de Schwann nociceptives, un gonflement des fibres de Remak et une hypomyélinisation), ainsi qu’une accumulation de lipides dans les nerfs due à la surexpression du transporteur CD36. Ces modifications s’accompagnent de dysfonctionnements mitochondriaux et d’une accumulation d’acylcarnitines, suggérant un lien entre déséquilibre lipidique et neurodégénérescence. Cette découverte souligne l’importance de la PCSK9 dans l’homéostasie nerveuse et ouvre des pistes pour comprendre certaines neuropathies.
Mots-clés : Cholestérol, Métabolisme, Neuropathie, Douleur, PCSK9.
Mots-clés : Cholestérol, Métabolisme, Neuropathie, Douleur, PCSK9.
JCI INSIGHT
2025 MAY 8;10(12):E183786.
DOI: 10.1172/JCI.INSIGHT.183786. ECOLLECTION 2025 JUN 23.
PCSK9 deficiency promotes the development of peripheral neuropathy
Ali K Jaafar 1, Aurélie Paulo-Ramos 1, Guillaume Rastoldo 1, Bryan Veeren 1, Cynthia Planesse 1, Matthieu Bringart 1, Philippe Rondeau 1, Kévin Chemello 1, Olivier Meilhac 1 2, Gilles C Lambert 1, Steeve Bourane 1
Affiliations
Abstract : Proprotein convertase subtilisin/kexin type 9 (PCSK9) induces the hepatic degradation of the low-density lipoprotein receptor (LDLR), thereby increasing the concentration of LDL-cholesterol 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 effect of PCSK9 on the peripheral nervous system remains 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 reduced thermal and mechanical pain sensations. PCSK9-deficient mice also presented with skin structural changes, including a reduction in nociceptive Schwann cell number, axonal swelling of Remak fibers, and hypomyelination of small nerve fibers. Interestingly, the peripheral nerves of PCSK9-deficient mice showed an upregulation of CD36, a fatty acid transporter, which correlated with increased nerve lipid content, structural mitochondrial abnormalities, and acylcarnitine accumulation. Our findings demonstrate that PCSK9 plays a critical role in peripheral nerves by regulating lipid homeostasis and that its deficiency results in symptoms related to peripheral neuropathy.
Keywords: Cholesterol; Metabolism; Neurodegeneration; Neuroscience; Pain.
Affiliations
- 1Université de La Réunion, INSERM, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Pierre, La Réunion, France.
- 2CHU de La Réunion, Saint-Pierre, France.
Abstract : Proprotein convertase subtilisin/kexin type 9 (PCSK9) induces the hepatic degradation of the low-density lipoprotein receptor (LDLR), thereby increasing the concentration of LDL-cholesterol 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 effect of PCSK9 on the peripheral nervous system remains 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 reduced thermal and mechanical pain sensations. PCSK9-deficient mice also presented with skin structural changes, including a reduction in nociceptive Schwann cell number, axonal swelling of Remak fibers, and hypomyelination of small nerve fibers. Interestingly, the peripheral nerves of PCSK9-deficient mice showed an upregulation of CD36, a fatty acid transporter, which correlated with increased nerve lipid content, structural mitochondrial abnormalities, and acylcarnitine accumulation. Our findings demonstrate that PCSK9 plays a critical role in peripheral nerves by regulating lipid homeostasis and that its deficiency results in symptoms related to peripheral neuropathy.
Keywords: Cholesterol; Metabolism; Neurodegeneration; Neuroscience; Pain.