PCSK9 and the nervous system: a no-brainer?

Jaafar, Ali K.; Techer, Romuald; Chemello, Kévin; Lambert, Gilles; Bourane, Steeve

doi:10.1016/j.jlr.2023.100426

Cited by 7 publications

(3 citation statements)

References 105 publications

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“…It is worth mentioning, that a neurological complication, namely peripheral neuropathy has been described in subjects with prediabetes after application of PCSK9i ( 21 ). The role of PCSK9 and PCSK9 inhibition in the peripheral nervous system has been recently summarised ( 22 ). In non-mammalian models, knocking down the PCSK9 results in defective neurogenesis and is lethal ( 23 ).…”

Section: Discussion and Literature Reviewmentioning

confidence: 99%

Case Report: Neurological adverse events in subject with myasthenia gravis after PCSK9 inhibitor administration

Adámková,

Vitásková,

Hubáček

2024

Front. Cardiovasc. Med.

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BackgroundMyasthenia gravis is a rare chronic autoimmune neuromuscular disorder mainly caused by autoantibodies to the nicotinic acetylcholine receptor. Cholesterol is an essential molecule that affects the distribution and proper functioning of this receptor. Several reports have described the potential worsening of myasthenia gravis in patients treated with statins.Case presentationThe patient was an obese 72 years old man, past smoker, diagnosed with ischaemic heart disease, type 2 diabetes mellitus and lipid metabolism disorder. Statin treatment was not implemented because of chronic myasthenia gravis and PCSK9i monotherapy [Repatha (evolucamab), 140 mg] was implemented to treat dyslipidaemia. Within 24 h after the first dose of PCSK9i the patient developed severe muscle weakness, joint pain, fever, and general discomfort, lasting for several days. Despite strong advice against the second dose administration, this was self-administered approximately 2 weeks later, leading to report significant worsening of the muscle problems, leading to the patient admittion to the neurology department where he was being treated for myasthenia gravis attack.ConclusionBased on the neurologist's conclusion, it can be assumed that in this case, treatment with PCSK9i resulted in significant worsening of the patient's chronic disease.

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Section: Discussion and Literature Reviewmentioning

confidence: 99%

Case Report: Neurological adverse events in subject with myasthenia gravis after PCSK9 inhibitor administration

Adámková,

Vitásková,

Hubáček

2024

Front. Cardiovasc. Med.

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“…Furthermore, PCSK9, functioning as a circulating inhibitor of LDLR, assumes a significant role not only within the CNS but also within the peripheral nervous system (PNS). PCSK9 possesses the capacity to influence immune cell activation within the brain, induce alterations in brain inflammatory responses, and emerge as a novel therapeutic target for addressing brain inflammation ( 323 , 324 ). Administering PCSK9 inhibitors via intravenous injection can diminish the expression of NF-κB, ameliorate the proliferation and hypertrophy of microglia and astrocytes, and impede neuroinflammation ( 325 ).…”

Section: Liver and Diseasesmentioning

confidence: 99%

Interorgan communication with the liver: novel mechanisms and therapeutic targets

Zhao,

Zhang,

et al. 2023

Front. Immunol.

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The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as “hepatokines”). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body’s innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.

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“…PCSK9 is primarily expressed by the liver and circulating PCSK9 is almost exclusively of hepatic origin 6 , but the protein is expressed in several other tissues, including the intestine, kidneys, pancreas, and the nervous system 7,8 . PCSK9 was initially cloned in cerebellar neurons undergoing apoptosis and originally called Neural Apoptosis-Regulated Convertase-1 (NARC-1) 7 .…”

Section: Introductionmentioning

confidence: 99%

PCSK9 deficiency promotes the development of peripheral neuropathy

Jaafar,

Paulo-Ramos,

Rastoldo

et al. 2024

Preprint

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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.

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PCSK9 and the nervous system: a no-brainer?

Cited by 7 publications

References 105 publications

Case Report: Neurological adverse events in subject with myasthenia gravis after PCSK9 inhibitor administration

Case Report: Neurological adverse events in subject with myasthenia gravis after PCSK9 inhibitor administration

Interorgan communication with the liver: novel mechanisms and therapeutic targets

PCSK9 deficiency promotes the development of peripheral neuropathy

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